Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies

Topic Information

Dear Colleagues,

The increase in antibiotic resistance raises concerns that, at least in some regions (especially developing countries), we are returning to a pre-antibiotic era, in particular for Gram-negative infections. The CV-19 outbreak exemplifies that resistance originating from some parts of the world has global effects, hence we need to act now to eradicate antimicrobial resistance worldwide. There are few novel anti-Gram-negative/positive drugs entering clinical trials, therefore, novel drugs, but also development of novel techniques and methods that lead to new drugs, are needed. Overcoming resistance to restore the activity of existing drugs and repurposing with an excellent safety record are also important topics. This Special Issue is seeking original research articles and synopses (reviews) that make substantial advances within this field and we are inviting researchers from different fields (chemistry, biology, biochemistry, medicinal chemistry, PK PD modellers) to contribute to this editorial project. We aim to cover not only traditional but also non-traditional products, with both broad range and single target antibiotics both for human and animal use.

Dr. Daniele Castagnolo
Dr. Jürgen Brem
Prof. Dr. Mark G. Moloney
Dr. Sónia Silva
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Antibiotics antibiotics	4.3	7.3	2012	15.8 Days	CHF 2900
Chemistry chemistry	2.4	3.2	2019	17.2 Days	CHF 1800
Molecules molecules	4.2	7.4	1996	15.1 Days	CHF 2700

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Published Papers (61 papers)

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21 pages, 3266 KiB  

Open AccessArticle

Antiplasmodial Cyclodecapeptides from Tyrothricin Share a Target with Chloroquine

by Adrienne N.-N. Leussa and Marina Rautenbach

Antibiotics 2022, 11(6), 801; https://doi.org/10.3390/antibiotics11060801 - 14 Jun 2022

Cited by 3 | Viewed by 3019

Abstract

Previous research found that the six major cyclodecapeptides from the tyrothricin complex, produced by Brevibacillus parabrevis, showed potent activity against chloroquine sensitive (CQS) Plasmodium falciparum. The identity of the aromatic residues in the aromatic dipeptide unit in cyclo-(D-Phe¹-Pro² [...] Read more.

Previous research found that the six major cyclodecapeptides from the tyrothricin complex, produced by Brevibacillus parabrevis, showed potent activity against chloroquine sensitive (CQS) Plasmodium falciparum. The identity of the aromatic residues in the aromatic dipeptide unit in cyclo-(D-Phe¹-Pro²-(Phe³/Trp³)-D-Phe⁴/D-Trp⁴)-Asn⁵-Gln⁶-(Tyr⁷/Phe⁷/Trp⁷)-Val⁸-(Orn⁹/Lys⁹)-Leu¹⁰ was proposed to have an important role in activity. CQS and resistant (CQR) P. falciparum strains were challenged with three representative cyclodecapeptides. Our results confirmed that cyclodecapeptides from tyrothricin had significantly higher antiplasmodial activity than the analogous gramicidin S, rivaling that of CQ. However, the previously hypothesized size and hydrophobicity dependent activity for these peptides did not hold true for P. falciparum strains, other than for the CQS 3D7 strain. The Tyr⁷ in tyrocidine A (TrcA) with Phe³-D-Phe⁴ seem to be related with loss in activity correlating with CQ antagonism and resistance, indicating a shared target and/or resistance mechanism in which the phenolic groups play a role. Phe⁷ in phenycidine A, the second peptide containing Phe³-D-Phe⁴, also showed CQ antagonism. Conversely, Trp⁷ in tryptocidine C (TpcC) with Trp³-D-Trp⁴ showed improved peptide selectivity and activity towards the more resistant strains, without overt antagonism towards CQ. However, TpcC lead to similar parasite stage inhibition and parasite morphology changes than previously observed for TrcA. The disorganization of chromatin packing and neutral lipid structures, combined with amorphous hemozoin crystals, could account for halted growth in late trophozoite/early schizont stage and the nanomolar non-lytic activity of these peptides. These targets related to CQ antagonism, changes in neural lipid distribution, leading to hemozoin malformation, indicate that the tyrothricin cyclodecapeptides and CQ share a target in the malaria parasite. The differing activities of these cyclic peptides towards CQS and CQR P. falciparum strains could be due to variable target interaction in multiple modes of activity. This indicated that the cyclodecapeptide activity and parasite resistance response depended on the aromatic residues in positions 3, 4 and 7. This new insight on these natural cyclic decapeptides could also benefit the design of unique small peptidomimetics in which activity and resistance can be modulated. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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17 pages, 3390 KiB  

Open AccessArticle

TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens

by Eric J. Bryan, Hye Yeon Sagong, Ajit K. Parhi, Mark C. Grier, Jacques Y. Roberge, Edmond J. LaVoie and Daniel S. Pilch

Antibiotics 2022, 11(5), 693; https://doi.org/10.3390/antibiotics11050693 - 20 May 2022

Cited by 6 | Viewed by 2903

Abstract

The emergence of multi-drug-resistant Gram-negative pathogens highlights an urgent clinical need to explore and develop new antibiotics with novel antibacterial targets. MreB is a promising antibacterial target that functions as an essential elongasome protein in most Gram-negative bacterial rods. Here, we describe a [...] Read more.

The emergence of multi-drug-resistant Gram-negative pathogens highlights an urgent clinical need to explore and develop new antibiotics with novel antibacterial targets. MreB is a promising antibacterial target that functions as an essential elongasome protein in most Gram-negative bacterial rods. Here, we describe a third-generation MreB inhibitor (TXH11106) with enhanced bactericidal activity versus the Gram-negative pathogens Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa compared to the first- and second-generation compounds A22 and CBR-4830, respectively. Large inocula of these four pathogens are associated with a low frequency of resistance (FOR) to TXH11106. The enhanced bactericidal activity of TXH11106 relative to A22 and CBR-4830 correlates with a correspondingly enhanced capacity to inhibit E. coli MreB ATPase activity via a noncompetitive mechanism. Morphological changes induced by TXH11106 in E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa provide further evidence supporting MreB as the bactericidal target of the compound. Taken together, our results highlight the potential of TXH11106 as an MreB inhibitor with activity against a broad spectrum of Gram-negative bacterial pathogens of acute clinical importance. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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15 pages, 1598 KiB  

Open AccessEditor’s ChoiceArticle

Synergism between the Synthetic Antibacterial and Antibiofilm Peptide (SAAP)-148 and Halicin

by Miriam E. van Gent, Tanny J. K. van der Reijden, Patrick R. Lennard, Adriëtte W. de Visser, Bep Schonkeren-Ravensbergen, Natasja Dolezal, Robert A. Cordfunke, Jan Wouter Drijfhout and Peter H. Nibbering

Antibiotics 2022, 11(5), 673; https://doi.org/10.3390/antibiotics11050673 - 17 May 2022

Cited by 15 | Viewed by 4421

Abstract

Recently, using a deep learning approach, the novel antibiotic halicin was discovered. We compared the antibacterial activities of two novel bactericidal antimicrobial agents, i.e., the synthetic antibacterial and antibiofilm peptide (SAAP)-148 with this antibiotic halicin. Results revealed that SAAP-148 was more effective than [...] Read more.

Recently, using a deep learning approach, the novel antibiotic halicin was discovered. We compared the antibacterial activities of two novel bactericidal antimicrobial agents, i.e., the synthetic antibacterial and antibiofilm peptide (SAAP)-148 with this antibiotic halicin. Results revealed that SAAP-148 was more effective than halicin in killing planktonic bacteria of antimicrobial-resistant (AMR) Escherichia coli, Acinetobacter baumannii and Staphylococcus aureus, especially in biologically relevant media, such as plasma and urine, and in 3D human infection models. Surprisingly, SAAP-148 and halicin were equally effective against these bacteria residing in immature and mature biofilms. As their modes of action differ, potential favorable interactions between SAAP-148 and halicin were investigated. For some specific strains of AMR E. coli and S. aureus synergism between these agents was observed, whereas for other strains, additive interactions were noted. These favorable interactions were confirmed for AMR E. coli in a 3D human bladder infection model and AMR S. aureus in a 3D human epidermal infection model. Together, combinations of these two novel antimicrobial agents hold promise as an innovative treatment for infections not effectively treatable with current antibiotics. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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13 pages, 1793 KiB  

Open AccessArticle

Derivatives of Esculentin-1 Peptides as Promising Candidates for Fighting Infections from Escherichia coli O157:H7

by Raffaella Scotti, Bruno Casciaro, Annarita Stringaro, Fabrizio Morgia, Maria Luisa Mangoni and Roberta Gabbianelli

Antibiotics 2022, 11(5), 656; https://doi.org/10.3390/antibiotics11050656 - 13 May 2022

Cited by 8 | Viewed by 2670

Abstract

New strategies are needed to fight the emergence of multidrug-resistant bacteria caused by an overuse of antibiotics in medical and veterinary fields. Due to the importance of biofilms in clinical infections, antibiofilm peptides have a great potential to treat infections. In recent years, [...] Read more.

New strategies are needed to fight the emergence of multidrug-resistant bacteria caused by an overuse of antibiotics in medical and veterinary fields. Due to the importance of biofilms in clinical infections, antibiofilm peptides have a great potential to treat infections. In recent years, an increased interest has emerged in antimicrobial peptides (AMPs). One of the richest sources of AMPs is represented by amphibian skin. In the present work, we investigated the effects of two peptides derived from the frog skin AMP esculentin-1, namely, Esc(1-21) and Esc(1-18), on the growth, biofilm formation, and gene expression of the non-pathogenic Escherichia coli strain K12 and of enterohemorrhagic E. coli O157:H7. Both peptides showed minimal bactericidal concentrations ranging from 4 to 8 µM for Esc(1-21) and from 32 to 64 µM for Esc(1-18). They also, at sub-MIC doses, reduced the formation of biofilm, as supported by both microbiological assays and scanning electron microscopy, while they displayed no marked activity against the planktonic form of the bacteria. Transcriptional analysis in E. coli O157:H7 showed that both AMPs induced the expression of several genes involved in the regulation of formation and dispersal of biofilm, as well as in the stress response. In conclusion, we demonstrated that these AMPs affect E. coli O157:H7 growth and biofilm formation, thus suggesting a great potential to be developed as novel therapeutics against infections caused by bacterial biofilms. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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19 pages, 2091 KiB  

Open AccessReview

Phytochemical Profile of Antibacterial Agents from Red Betel Leaf (Piper crocatum Ruiz and Pav) against Bacteria in Dental Caries

by Leny Heliawati, Seftiana Lestari, Uswatun Hasanah, Dwipa Ajiati and Dikdik Kurnia

Molecules 2022, 27(9), 2861; https://doi.org/10.3390/molecules27092861 - 30 Apr 2022

Cited by 20 | Viewed by 5611

Abstract

Based on data from The Global Burden of Disease Study in 2016, dental and oral health problems, especially dental caries, are a disease experienced by almost half of the world’s population (3.58 billion people). One of the main causes of dental caries is [...] Read more.

Based on data from The Global Burden of Disease Study in 2016, dental and oral health problems, especially dental caries, are a disease experienced by almost half of the world’s population (3.58 billion people). One of the main causes of dental caries is the pathogenesis of Streptococcus mutans. Prevention can be achieved by controlling S. mutans using an antibacterial agent. The most commonly used antibacterial for the treatment of dental caries is chlorhexidine. However, long-term use of chlorhexidine has been reported to cause resistance and some side effects. Therefore, the discovery of a natural antibacterial agent is an urgent need. A natural antibacterial agent that can be used are herbal medicines derived from medicinal plants. Piper crocatum Ruiz and Pav has the potential to be used as a natural antibacterial agent for treating dental and oral health problems. Several studies reported that the leaves of P. crocatum Ruiz and Pav contain secondary metabolites such as essential oils, flavonoids, alkaloids, terpenoids, tannins, and phenolic compounds that are active against S. mutans. This review summarizes some information about P. crocatum Ruiz and Pav, various isolation methods, bioactivity, S. mutans bacteria that cause dental caries, biofilm formation mechanism, antibacterial properties, and the antibacterial mechanism of secondary metabolites in P. crocatum Ruiz and Pav. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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22 pages, 7764 KiB  

Open AccessArticle

Rhamnolipid Nano-Micelles versus Alcohol-Based Hand Sanitizer: A Comparative Study for Antibacterial Activity against Hospital-Acquired Infections and Toxicity Concerns

by Yasmin Abo-zeid, Marwa Reda Bakkar, Gehad E. Elkhouly, Nermeen R. Raya and Dalia Zaafar

Antibiotics 2022, 11(5), 605; https://doi.org/10.3390/antibiotics11050605 - 29 Apr 2022

Cited by 15 | Viewed by 4749

Abstract

Hospital-acquired infections (HAIs) are considered to be a major global healthcare challenge, in large part because of the development of microbial resistance to currently approved antimicrobial drugs. HAIs are frequently preventable through infection prevention and control measures, with hand hygiene as a key [...] Read more.

Hospital-acquired infections (HAIs) are considered to be a major global healthcare challenge, in large part because of the development of microbial resistance to currently approved antimicrobial drugs. HAIs are frequently preventable through infection prevention and control measures, with hand hygiene as a key activity. Improving hand hygiene was reported to reduce the transmission of healthcare-associated pathogens and HAIs. Alcohol-based hand sanitizers are commonly used due to their rapid action and broad spectrum of microbicidal activity, offering protection against bacteria and viruses. However, their frequent administration has been reported to be associated with many side effects, such as skin sensitivity, skin drying, and cracks, which promote further skin infections. Thus, there is an essential need to find alternative approaches to hand sanitation. Rhamnolipids are glycolipids produced by Pseudomonas aeruginosa, and were shown to have broad antimicrobial activity as biosurfactants. We have previously demonstrated the antimicrobial activity of rhamnolipid nano-micelles against selected drug-resistant Gram-negative (Salmonella Montevideo and Salmonella Typhimurium) and Gram-positive bacteria (Staphylococcus aureus, Streptococcus pneumoniae). To the best of our knowledge, the antimicrobial activity of rhamnolipid nano-micelles in comparison to alcohol-based hand sanitizers against microorganisms commonly causing HAIs in Egypt—such as Acinetobacter baumannii and Staphylococcus aureus—has not yet been studied. In the present work, a comparative study of the antibacterial activity of rhamnolipid nano-micelles versus alcohol-based hand sanitizers was performed, and their safety profiles were also assessed. It was demonstrated that rhamnolipid nano-micelles had a comparable antibacterial activity to alcohol-based hand sanitizer, with a better safety profile, i.e., rhamnolipid nano-micelles are unlikely to cause any harmful effects on the skin. Thus, rhamnolipid nano-micelles could be recommended to replace alcohol-based hand sanitizers; however, they must still be tested by healthcare workers in healthcare settings to ascertain their antimicrobial activity and safety. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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19 pages, 3531 KiB  

Open AccessArticle

Design, Synthesis and Biological Evaluation of N-phenylindole Derivatives as Pks13 Inhibitors againstMycobacterium tuberculosis

by Yanpeng Cai, Wei Zhang, Shichun Lun, Tongtong Zhu, Weijun Xu, Fan Yang, Jie Tang, William R. Bishai and Lifang Yu

Molecules 2022, 27(9), 2844; https://doi.org/10.3390/molecules27092844 - 29 Apr 2022

Cited by 9 | Viewed by 3185

Abstract

Polyketide synthase 13 (Pks13), an essential enzyme for the survival of Mycobacterium tuberculosis (Mtb), is an attractive target for new anti-TB agents. In our previous work, we have identified 2-phenylindole derivatives against Mtb. The crystallography studies demonstrated that the two-position [...] Read more.

Polyketide synthase 13 (Pks13), an essential enzyme for the survival of Mycobacterium tuberculosis (Mtb), is an attractive target for new anti-TB agents. In our previous work, we have identified 2-phenylindole derivatives against Mtb. The crystallography studies demonstrated that the two-position phenol was solvent-exposed in the Pks13-TE crystal structure and a crucial hydrogen bond was lost while introducing bulkier hydrophobic groups at indole N moieties. Thirty-six N-phenylindole derivatives were synthesized and evaluated for antitubercular activity using a structure-guided approach. The structure–activity relationship (SAR) studies resulted in the discovery of the potent Compounds 45 and 58 against Mtb H37Rv, with an MIC value of 0.0625 μg/mL and 0.125 μg/mL, respectively. The thermal stability analysis showed that they bind with high affinity to the Pks13-TE domain. Preliminary ADME evaluation showed that Compound 58 displayed modest human microsomal stability. This report further validates that targeting Pks13 is a valid strategy for the inhibition of Mtb and provides a novel scaffold for developing leading anti-TB compounds. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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14 pages, 1729 KiB  

Open AccessArticle

Hydroxyapatite/TiO₂ Nanomaterial with Defined Microstructural and Good Antimicrobial Properties

by Miljana Mirković, Suzana Filipović, Ana Kalijadis, Pavle Mašković, Jelena Mašković, Branislav Vlahović and Vladimir Pavlović

Antibiotics 2022, 11(5), 592; https://doi.org/10.3390/antibiotics11050592 - 28 Apr 2022

Cited by 12 | Viewed by 2656

Abstract

Due to the growing number of people infected with the new coronavirus globally, which weakens immunity, there has been an increase in bacterial infections. Hence, knowledge about simple and low-cost synthesis methods of materials with good structural and antimicrobial properties is of great [...] Read more.

Due to the growing number of people infected with the new coronavirus globally, which weakens immunity, there has been an increase in bacterial infections. Hence, knowledge about simple and low-cost synthesis methods of materials with good structural and antimicrobial properties is of great importance. A material obtained through the combination of a nanoscale hydroxyapatite material (with good biocompatibility) and titanium dioxide (with good degradation properties of organic molecules) can absorb and decompose bacteria. In this investigation, three different synthesis routes used to prepare hydroxyapatite/titanium dioxide nanomaterials are examined. The morphology and semiquantitative chemical composition are characterized by scanning electron microscopy with energy dispersive X-ray analysis (SEM-EDX). The obtained materials’ phase and structural characterization are determined using the X-ray powder diffraction method (XRD). The crystallite sizes of the obtained materials are in the range of 8 nm to 15 nm. Based on XRD peak positions, the hexagonal hydroxyapatite phases are formed in all samples along with TiO₂ anatase and rutile phases. According to SEM and TEM analyses, the morphology of the prepared samples differs depending on the synthesis route. The EDX analysis confirmed the presence of Ti, Ca, P, and O in the obtained materials. The IR spectroscopy verified the vibration bands characteristic for HAp and titanium. The investigated materials show excellent antimicrobial and photocatalytic properties. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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17 pages, 5325 KiB  

Open AccessArticle

Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design Approaches

by Manvi Singh, Priya Kempanna and Kavitha Bharatham

Molecules 2022, 27(9), 2805; https://doi.org/10.3390/molecules27092805 - 28 Apr 2022

Cited by 2 | Viewed by 2762

Abstract

Targeting enzymes that play a role in the biosynthesis of the bacterial cell wall has long been a strategy for antibacterial discovery. In particular, the cell wall of Mycobacterium tuberculosis (Mtb) is a complex of three layers, one of which is Peptidoglycan, an [...] Read more.

Targeting enzymes that play a role in the biosynthesis of the bacterial cell wall has long been a strategy for antibacterial discovery. In particular, the cell wall of Mycobacterium tuberculosis (Mtb) is a complex of three layers, one of which is Peptidoglycan, an essential component providing rigidity and strength. UDP-GlcNAc, a precursor for the synthesis of peptidoglycan, is formed by GlmU, a bi-functional enzyme. Inhibiting GlmU Uridyltransferase activity has been proven to be an effective anti-bacterial, but its similarity with human enzymes has been a deterrent to drug development. To develop Mtb selective hits, the Mtb GlmU substrate binding pocket was compared with structurally similar human enzymes to identify selectivity determining factors. Substrate binding pockets and conformational changes upon substrate binding were analyzed and MD simulations with substrates were performed to quantify crucial interactions to develop critical pharmacophore features. Thereafter, two strategies were applied to propose potent and selective bacterial GlmU Uridyltransferase domain inhibitors: (i) optimization of existing inhibitors, and (ii) identification by virtual screening. The binding modes of hits identified from virtual screening and ligand growing approaches were evaluated further for their ability to retain stable contacts within the pocket during 20 ns MD simulations. Hits that are predicted to be more potent than existing inhibitors and selective against human homologues could be of great interest for rejuvenating drug discovery efforts towards targeting the Mtb cell wall for antibacterial discovery. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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6 pages, 537 KiB  

Open AccessCommunication

Cefiderocol Protects against Cytokine- and Endotoxin-Induced Disruption of Vascular Endothelial Cell Integrity in an In Vitro Experimental Model

by Dagmar Hildebrand, Jana Böhringer, Eva Körner, Ute Chiriac, Sandra Förmer, Aline Sähr, Torsten Hoppe-Tichy, Klaus Heeg and Dennis Nurjadi

Antibiotics 2022, 11(5), 581; https://doi.org/10.3390/antibiotics11050581 - 26 Apr 2022

Cited by 4 | Viewed by 8139

Abstract

The severe course of bloodstream infections with Gram-negative bacilli can lead to organ dysfunctions and compromise the integrity of the vascular barrier, which are the hallmarks of sepsis. This study aimed to investigate the potential effect of cefiderocol on the barrier function of [...] Read more.

The severe course of bloodstream infections with Gram-negative bacilli can lead to organ dysfunctions and compromise the integrity of the vascular barrier, which are the hallmarks of sepsis. This study aimed to investigate the potential effect of cefiderocol on the barrier function of vascular endothelial cells (vECs) in an in vitro experimental set-up. Human umbilical vein cells (HUVECs), co-cultured with erythrocyte-depleted whole blood for up to 48 h, were activated with tumor necrosis factor-alpha (TNF-α) or lipopolysaccharide (LPS) to induce endothelial damage in the absence or presence of cefiderocol (concentrations of 10, 40 and 70 mg/L). The endothelial integrity was quantified using transendothelial electrical resistance (TEER) measurement, performed at 0, 3, 24 and 48 h after stimulation. Stimulation with TNF-α and LPS increased the endothelial permeability assessed by TEER at 24 and 48 h of co-culture. Furthermore, cefiderocol reduces interleukin-6 (IL-6), interleukin-1β (IL-1β) and TNF-α release in peripheral blood mononuclear cells (PBMCs) following LPS stimulation in a dose-dependent manner. Collectively, the data suggest that cefiderocol may have an influence on the cellular immune response and might support the maintenance of vEC integrity during inflammation associated with infection with Gram-negative bacteria, which warrants further investigations. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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13 pages, 3137 KiB  

Open AccessArticle

Investigating the Antibacterial Characteristics of Japanese Bamboo

by Raviduth Ramful, Thefye P. M. Sunthar, Kaeko Kamei and Giuseppe Pezzotti

Antibiotics 2022, 11(5), 569; https://doi.org/10.3390/antibiotics11050569 - 24 Apr 2022

Cited by 5 | Viewed by 4092

Abstract

Natural materials, such as bamboo, is able to withstand the rough conditions posed by its environment, such as resistance to degradation by microorganisms, due to notable antibacterial characteristics. The methods of extraction exert a significant influence on the effectiveness of bamboo-derived antibacterial agents. [...] Read more.

Natural materials, such as bamboo, is able to withstand the rough conditions posed by its environment, such as resistance to degradation by microorganisms, due to notable antibacterial characteristics. The methods of extraction exert a significant influence on the effectiveness of bamboo-derived antibacterial agents. In this study, the antibacterial characteristics of various types of Japanese bamboo, namely, Kyoto-Moso, Kyushu-Moso and Kyushu-Madake were investigated by considering an extraction and a non-extraction method. The characterization of the efficacy of antibacterial agents of various bamboo samples derived from both methods of extractions was conducted using an in vitro cultured bacteria technique consisting of E. coli and S. aureus. Antibacterial test results based on colony-forming units showed that antibacterial agents derived from the non-extraction method yielded better efficacy when tested against E. coli and S. aureus. Most specimens displayed maximum antibacterial efficacy following a 48-h period. The antibacterial agents derived from thermally modified bamboo powder via the non-extraction method showed improved antibacterial activity against S. aureus specifically. In contrast, absorbance results indicated that antibacterial agents derived from the extraction method yielded poor efficacy when tested against both E. coli and S. aureus. From FTIR analysis, characteristic bands assigned to the C-O and C-H functional groups in lignin were recognized as responsible for the antibacterial trait observed in both natural and thermally modified Japanese bamboo powder. Techniques to exploit the antibacterial characteristics present in bamboo by identification of antibacterial source and adoption of adequate methods of extraction are key steps in taking advantage of this attribute in numerous applications involving bamboo-derived products such as laminates and textile fabrics. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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12 pages, 4827 KiB  

Open AccessArticle

In Silico and In Vitro Antimalarial Screening and Validation Targeting Plasmodium falciparum Plasmepsin V

by Xin Ji, Zhensheng Wang, Qianqian Chen, Jingzhong Li, Heng Wang, Zenglei Wang and Lan Yang

Molecules 2022, 27(9), 2670; https://doi.org/10.3390/molecules27092670 - 21 Apr 2022

Cited by 5 | Viewed by 2731

Abstract

Malaria chemotherapy is greatly threatened by the recent emergence and spread of resistance in the Plasmodium falciparum parasite against artemisinins and their partner drugs. Therefore, it is an urgent priority to develop new antimalarials. Plasmepsin V (PMV) is regarded as a superior drug [...] Read more.

Malaria chemotherapy is greatly threatened by the recent emergence and spread of resistance in the Plasmodium falciparum parasite against artemisinins and their partner drugs. Therefore, it is an urgent priority to develop new antimalarials. Plasmepsin V (PMV) is regarded as a superior drug target for its essential role in protein export. In this study, we performed virtual screening based on homology modeling of PMV structure, molecular docking and pharmacophore model analysis against a library with 1,535,478 compounds, which yielded 233 hits. Their antimalarial activities were assessed amongst four non-peptidomimetic compounds that demonstrated the promising inhibition of parasite growth, with mean IC₅₀ values of 6.67 μM, 5.10 μM, 12.55 μM and 8.31 μM. No significant affection to the viability of L929 cells was detected in these candidates. These four compounds displayed strong binding activities with the PfPMV model through H-bond, hydrophobic, halogen bond or π-π interactions in molecular docking, with binding scores under −9.0 kcal/mol. The experimental validation of molecule-protein interaction identified the binding of four compounds with multiple plasmepsins; however, only compound 47 showed interaction with plasmepsin V, which exhibited the potential to be developed as an active PfPMV inhibitor. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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18 pages, 3314 KiB  

Open AccessArticle

Computational Insights and In Vitro Validation of Antibacterial Potential of Shikimate Pathway-Derived Phenolic Acids as NorA Efflux Pump Inhibitors

by Karishma Singh, Roger M. Coopoosamy, Njabulo J. Gumede and Saheed Sabiu

Molecules 2022, 27(8), 2601; https://doi.org/10.3390/molecules27082601 - 18 Apr 2022

Cited by 14 | Viewed by 2799

Abstract

The expression of the efflux pump systems is the most important mechanism of antibiotic resistance in bacteria, as it contributes to reduced concentration and the subsequent inactivity of administered antibiotics. NorA is one of the most studied antibacterial targets used as a model [...] Read more.

The expression of the efflux pump systems is the most important mechanism of antibiotic resistance in bacteria, as it contributes to reduced concentration and the subsequent inactivity of administered antibiotics. NorA is one of the most studied antibacterial targets used as a model for efflux-mediated resistance. The present study evaluated shikimate pathway-derived phenolic acids against NorA (PDB ID: 1PW4) as a druggable target in antibacterial therapy using in silico modelling and in vitro methods. Of the 22 compounds evaluated, sinapic acid (−9.0 kcal/mol) and p-coumaric acid (−6.3 kcal/mol) had the best and most prominent affinity for NorA relative to ciprofloxacin, a reference standard (−4.9 kcal/mol). A further probe into the structural stability and flexibility of the resulting NorA-phenolic acids complexes through molecular dynamic simulations over a 100 ns period revealed p-coumaric acid as the best inhibitor of NorA relative to the reference standard. In addition, both phenolic acids formed H-bonds with TYR 76, a crucial residue implicated in NorA efflux pump inhibition. Furthermore, the phenolic acids demonstrated favourable drug likeliness and conformed to Lipinski’s rule of five for ADME properties. For the in vitro evaluation, the phenolic acids had MIC values in the range 31.2 to 62.5 μg/mL against S. aureus, and E. coli, and there was an overall reduction in MIC following their combination with ciprofloxacin. Taken together, the findings from both the in silico and in vitro evaluations in this study have demonstrated high affinity of p-coumaric acid towards NorA and could be suggestive of its exploration as a novel NorA efflux pump inhibitor. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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14 pages, 1849 KiB  

Open AccessArticle

The Isolation and Characterization of Antagonist Trichoderma spp. from the Soil of Abha, Saudi Arabia

by Aisha Saleh Alwadai, Kahkashan Perveen and Mona Alwahaibi

Molecules 2022, 27(8), 2525; https://doi.org/10.3390/molecules27082525 - 14 Apr 2022

Cited by 15 | Viewed by 4450

Abstract

Background: The genus Trichoderma is widely spread in the environment, mainly in soils. Trichoderma are filamentous fungi and are used in a wide range of fields to manage plant patho-genic fungi. They have proven to be effective biocontrol agents due to their [...] Read more.

Background: The genus Trichoderma is widely spread in the environment, mainly in soils. Trichoderma are filamentous fungi and are used in a wide range of fields to manage plant patho-genic fungi. They have proven to be effective biocontrol agents due to their high reproducibility, adaptability, efficient nutrient mobilization, ability to colonize the rhizosphere, significant inhibitory effects against phytopathogenic fungi, and efficacy in promoting plant growth. In the present study, the antagonist Trichoderma isolates were characterized from the soil of Abha region, Saudi Arabia. Methodology: Soil samples were collected from six locations of Abha, Saudi Arabia to isolate Trichoderma having the antagonistic potential against plant pathogenic fungi. The soil dilution plate method was used to isolate Trichoderma (Trichoderma Specific Medium (TSM)). Isolated Trichoderma were evaluated for their antagonistic potential against Fusarium oxysporum, Alternaria alternata and Helminthosporium rostratum. The antagonist activity was assessed by dual culture assay, and the effect of volatile metabolites and culture filtrate of Trichoderma. In addition, the effect of different temperature and salt concentrations on the growth of Trichoderma isolates were also evaluated. Results: The most potent Trichoderma species were identified by using ITS4 and ITS 5 primers. Total 48 Trichoderma isolates were isolated on (TSM) from the soil samples out of those six isolates were found to have antagonist potential against the tested plant pathogenic fungi. In general, Trichoderma strains A (1) 2.1 T, A (3) 3.1 T and A (6) 2.2 T were found to be highly effective in reducing the growth of tested plant pathogenic fungi. Trichoderma A (1) 2.1 T was highly effective against F. oxysporum (82%), whereas Trichoderma A (6) 2.2 T prevented the maximal growth of H. rostratum (77%) according to the dual culture data. Furthermore, Trichoderma A (1) 2.1 T volatile metabolites hindered F. oxysporum growth. The volatile metabolite of Trichoderma A (6) 2.2 T, on the other hand, had the strongest activity against A. alternata (45%). The Trichoderma A (1) 2.1 T culture filtrate was proven to be effective in suppressing the growth of H. rostratum (47%). The temperature range of 26 °C to 30 °C was observed to be optimum for Trichoderma growth. Trichoderma isolates grew well at salt concentrations (NaCl) of 2%, and with the increasing salt concentration the growth of isolates decreased. The molecular analysis of potent fungi by ITS4 and ITS5 primers confirmed that the Trichoderma isolates A (1) 2.1 T, A (3) 3.1 and A (6) 2.2 T were T. harzianum, T. brevicompactum, and T. velutinum, respectively. Conclusions: The study concludes that the soil of the Abha region contains a large population of diverse fungi including Trichoderma, which can be explored further to be used as biocontrol agents. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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19 pages, 4690 KiB  

Open AccessArticle

New Organic Salt from Levofloxacin-Citric Acid: What Is the Impact on the Stability and Antibiotic Potency?

by Ilma Nugrahani, Agnesya Namira Laksana, Hidehiro Uekusa and Hironaga Oyama

Molecules 2022, 27(7), 2166; https://doi.org/10.3390/molecules27072166 - 27 Mar 2022

Cited by 12 | Viewed by 4168

Abstract

This research dealt with the composition, structure determination, stability, and antibiotic potency of a novel organic salt composed of levofloxacin (LF) and citric acid (CA), named levofloxacin-citrate (LC). After a stoichiometric proportion screening, the antibiotic-antioxidant reaction was conducted by slow and fast evaporation [...] Read more.

This research dealt with the composition, structure determination, stability, and antibiotic potency of a novel organic salt composed of levofloxacin (LF) and citric acid (CA), named levofloxacin-citrate (LC). After a stoichiometric proportion screening, the antibiotic-antioxidant reaction was conducted by slow and fast evaporation methods. A series of characterizations using thermal analysis, powder X-ray diffractometry, vibrational spectroscopy, and nuclear magnetic resonance confirmed LC formation. The new organic salt showed a distinct thermogram and diffractogram. Next, Fourier transform infrared indicated the change in N-methylamine and carboxylic stretching, confirmed by ¹H nuclear magnetic resonance spectra to elucidate the 2D structure. Finally, single-crystal diffractometry determined LC as a new salt structure three-dimensionally. The attributive improvements were demonstrated on the stability toward the humidity and lighting of LC compared to LF alone. Moreover, the antibiotic potency of LF against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) enhanced ~1.5–2-fold by LC. Hereafter, LC is a potential salt antibiotic-antioxidant combination for dosage formulas development. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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13 pages, 1913 KiB  

Open AccessArticle

In Silico Screen Identifies a New Family of Agonists for the Bacterial Mechanosensitive Channel MscL

by Robin Wray, Paul Blount, Junmei Wang and Irene Iscla

Antibiotics 2022, 11(4), 433; https://doi.org/10.3390/antibiotics11040433 - 24 Mar 2022

Cited by 4 | Viewed by 3109

Abstract

MscL is a highly conserved mechanosensitive channel found in the majority of bacterial species, including pathogens. It functions as a biological emergency release valve, jettisoning solutes from the cytoplasm upon acute hypoosmotic stress. It opens the largest known gated pore and has been [...] Read more.

MscL is a highly conserved mechanosensitive channel found in the majority of bacterial species, including pathogens. It functions as a biological emergency release valve, jettisoning solutes from the cytoplasm upon acute hypoosmotic stress. It opens the largest known gated pore and has been heralded as an antibacterial target. Although there are no known endogenous ligands, small compounds have recently been shown to specifically bind to and open the channel, leading to decreased cell growth and viability. Their binding site is at the cytoplasmic/membrane and subunit interfaces of the protein, which has been recently been proposed to play an essential role in channel gating. Here, we have targeted this pocket using in silico screening, resulting in the discovery of a new family of compounds, distinct from other known MscL-specific agonists. Our findings extended the study of this functional region, the progression of MscL as a viable drug target, and demonstrated the power of in silico screening for identifying and improving the design of MscL agonists. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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20 pages, 4023 KiB  

Open AccessArticle

Identification of Putative Vaccine and Drug Targets against the Methicillin-Resistant Staphylococcus aureus by Reverse Vaccinology and Subtractive Genomics Approaches

by Romen Singh Naorem, Bandana Devi Pangabam, Sudipta Sankar Bora, Gunajit Goswami, Madhumita Barooah, Dibya Jyoti Hazarika and Csaba Fekete

Molecules 2022, 27(7), 2083; https://doi.org/10.3390/molecules27072083 - 24 Mar 2022

Cited by 26 | Viewed by 4845

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen and responsible for causing life-threatening infections. The emergence of hypervirulent and multidrug-resistant (MDR) S. aureus strains led to challenging issues in antibiotic therapy. Consequently, the morbidity and mortality rates caused by S. aureus infections have [...] Read more.

Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen and responsible for causing life-threatening infections. The emergence of hypervirulent and multidrug-resistant (MDR) S. aureus strains led to challenging issues in antibiotic therapy. Consequently, the morbidity and mortality rates caused by S. aureus infections have a substantial impact on health concerns. The current worldwide prevalence of MRSA infections highlights the need for long-lasting preventive measures and strategies. Unfortunately, effective measures are limited. In this study, we focus on the identification of vaccine candidates and drug target proteins against the 16 strains of MRSA using reverse vaccinology and subtractive genomics approaches. Using the reverse vaccinology approach, 4 putative antigenic proteins were identified; among these, PrsA and EssA proteins were found to be more promising vaccine candidates. We applied a molecular docking approach of selected 8 drug target proteins with the drug-like molecules, revealing that the ZINC4235426 as potential drug molecule with favorable interactions with the target active site residues of 5 drug target proteins viz., biotin protein ligase, HPr kinase/phosphorylase, thymidylate kinase, UDP-N-acetylmuramoyl-L-alanyl-D-glutamate-L-lysine ligase, and pantothenate synthetase. Thus, the identified proteins can be used for further rational drug or vaccine design to identify novel therapeutic agents for the treatment of multidrug-resistant staphylococcal infection. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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13 pages, 850 KiB  

Open AccessArticle

Antimicrobial Activity and 70S Ribosome Binding of Apidaecin-Derived Api805 with Increased Bacterial Uptake Rate

by Tobias Ludwig, Andor Krizsan, Gubran Khalil Mohammed and Ralf Hoffmann

Antibiotics 2022, 11(4), 430; https://doi.org/10.3390/antibiotics11040430 - 23 Mar 2022

Cited by 8 | Viewed by 3998

Abstract

In view of the global spread of multiresistant bacteria and the occurrence of panresistant bacteria, there is an urgent need for antimicrobials with novel modes of action. A promising class is antimicrobial peptides (AMPs), including them proline-rich AMPs (PrAMPs), which target the 70S [...] Read more.

In view of the global spread of multiresistant bacteria and the occurrence of panresistant bacteria, there is an urgent need for antimicrobials with novel modes of action. A promising class is antimicrobial peptides (AMPs), including them proline-rich AMPs (PrAMPs), which target the 70S ribosome to inhibit protein translation. Here, we present a new designer peptide, Api805, combining the N- and C-terminal sequences of PrAMPs Api137 and drosocin, respectively. Api805 was similarly active against two Escherichia coli B strains but was inactive against E. coli K12 strain BW25113. These different activities could not be explained by the dissociation constants measured for 70S ribosome preparations from E. coli K12 and B strains. Mutations in the SbmA transporter that PrAMPs use to pass the inner membrane or proteolytic degradation of Api805 by lysate proteases could not explain this either. Interestingly, Api805 seems not to bind to the known binding sites of PrAMPs at the 70S ribosome and inhibited in vitro protein translation, independent of release factors, most likely using a “multimodal effect”. Interestingly, Api805 entered the E. coli B strain Rosetta faster and at larger quantities than the E. coli K-12 strain BW25113, which may be related to the different LPS core structure. In conclusion, slight structural changes in PrAMPs significantly altered their binding sites and mechanisms of action, allowing for the design of different antibiotic classes. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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25 pages, 7034 KiB  

Open AccessArticle

Morphing Natural Product Platensimycin via Heck, Sonogashira, and One-Pot Sonogashira/Cycloaddition Reactions to Produce Antibiotics with In Vivo Activity

by Youchao Deng, Yuling Li, Zhongqing Wen, Claudia H. Ruiz, Xiang Weng, Michael D. Cameron, Yanwen Duan and Yong Huang

Antibiotics 2022, 11(4), 425; https://doi.org/10.3390/antibiotics11040425 - 23 Mar 2022

Cited by 2 | Viewed by 2710

Abstract

Type II fatty acid synthases are promising drug targets against major bacterial pathogens. Platensimycin (PTM) is a potent inhibitor against β-ketoacyl-[acyl carrier protein] synthase II (FabF) and β-ketoacyl-[acyl carrier protein] synthase I (FabB), while the poor pharmacokinetics has prevented its further [...] Read more.

Type II fatty acid synthases are promising drug targets against major bacterial pathogens. Platensimycin (PTM) is a potent inhibitor against β-ketoacyl-[acyl carrier protein] synthase II (FabF) and β-ketoacyl-[acyl carrier protein] synthase I (FabB), while the poor pharmacokinetics has prevented its further development. In this work, thirty-two PTM derivatives were rapidly prepared via Heck, Sonogashira, and one-pot Sonogashira/cycloaddition cascade reactions based on the Gram-scale synthesis of 6-iodo PTM (4). About half of the synthesized compounds were approximately equipotent to PTM against the tested Staphylococcus aureus strains. Among them, the representative compounds 4, A4, and B8 exhibited different plasma protein binding affinity or stability in the human hepatic microsome assay and showed improved in vivo efficacy over PTM in a mouse peritonitis model. In addition, A4 was also effective in an S. aureus-infected skin mouse model. Our study not only significantly expands the known PTM derivatives with improved antibacterial activities in vivo, but showcased that C–C cross-coupling reactions are useful tools to functionalize natural product drug leads. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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13 pages, 12614 KiB  

Open AccessArticle

Novel Antimicrobial Peptides Designed Using a Recurrent Neural Network Reduce Mortality in Experimental Sepsis

by Albert Bolatchiev, Vladimir Baturin, Evgeny Shchetinin and Elizaveta Bolatchieva

Antibiotics 2022, 11(3), 411; https://doi.org/10.3390/antibiotics11030411 - 18 Mar 2022

Cited by 17 | Viewed by 4360

Abstract

The search and development of new antibiotics is relevant due to widespread antibiotic resistance. One of the promising strategies is the de novo design of novel antimicrobial peptides. The amino acid sequences of 198 novel peptides were obtained using a generative long short-term [...] Read more.

The search and development of new antibiotics is relevant due to widespread antibiotic resistance. One of the promising strategies is the de novo design of novel antimicrobial peptides. The amino acid sequences of 198 novel peptides were obtained using a generative long short-term memory recurrent neural network (LSTM RNN). To assess their antimicrobial effect, we synthesized five out of 198 generated peptides. The PEP-38 and PEP-137 peptides were active in vitro against carbapenem-resistant isolates of Klebsiella aerogenes and K. pneumoniae. PEP-137 was also active against Pseudomonas aeruginosa. The remaining three peptides (PEP-36, PEP-136 and PEP-174) showed no antibacterial effect. Then the effect of PEP-38 and PEP-137 (a single intraperitoneal administration of a 100 μg dose 30 min after infection) on animal survival in an experimental murine model of K. pneumoniae-induced sepsis was investigated. As a control, two groups of mice were used: one received sterile saline, and the other received inactive in vitro PEP-36 (a single 100 μg dose). The PEP-36 peptide was shown to provide the highest survival rate (66.7%). PEP-137 showed a survival rate of 50%. PEP-38 was found to be ineffective. The data obtained can be used to develop new antibacterial peptide drugs to combat antibiotic resistance. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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21 pages, 8115 KiB  

Open AccessArticle

Inhibition of Filamentous Thermosensitive Mutant-Z Protein in Bacillus subtilis by Cyanobacterial Bioactive Compounds

by Manisha Gurnani, Prangya Rath, Abhishek Chauhan, Anuj Ranjan, Arabinda Ghosh, Rup Lal, Nobendu Mukerjee, Nada H. Aljarba, Saad Alkahtani, Vishnu D. Rajput, Svetlana Sushkova, Evgenya V. Prazdnova, Tatiana Minkina and Tanu Jindal

Molecules 2022, 27(6), 1907; https://doi.org/10.3390/molecules27061907 - 15 Mar 2022

Cited by 3 | Viewed by 4217

Abstract

Antibiotic resistance is one of the major growing concerns for public health. Conventional antibiotics act on a few predefined targets and, with time, several bacteria have developed resistance against a large number of antibiotics. The WHO has suggested that antibiotic resistance is at [...] Read more.

Antibiotic resistance is one of the major growing concerns for public health. Conventional antibiotics act on a few predefined targets and, with time, several bacteria have developed resistance against a large number of antibiotics. The WHO has suggested that antibiotic resistance is at a crisis stage and identification of new antibiotics and targets could be the only approach to bridge the gap. Filamentous Temperature Sensitive-Mutant Z (Fts-Z) is one of the promising and less explored antibiotic targets. It is a highly conserved protein and plays a key role in bacterial cell division by introducing a cytokinetic Z-ring formation. In the present article, the potential of over 165 cyanobacterial compounds with reported antibiotic activity against the catalytic core domain in the Fts-Z protein of the Bacillus subtilis was studied. The identified cyanobacterial compounds were screened using the GLIDE module of Maestro v-2019-2 followed by 100-ns molecular dynamics (MD) simulation. Ranking of the potential compound was performed using dock score and MMGBSA based free energy. The study reported that the docking score of aphanorphine (−6.010 Kcalmol⁻¹) and alpha-dimorphecolic acid (ADMA) (−6.574 Kcalmol⁻¹) showed significant role with respect to the reported potential inhibitor PC190723 (−4.135 Kcalmol⁻¹). A 100 ns MD simulation infers that Fts-Z ADMA complex has a stable conformation throughout the progress of the simulation. Both the compounds, i.e., ADMA and Aphanorphine, were further considered for In-vitro validation by performing anti-bacterial studies against B. subtilis by agar well diffusion method. The results obtained through In-vitro studies confirm that ADMA, a small molecule of cyanobacterial origin, is a potential compound with an antibacterial activity that may act by inhibiting the novel target Fts-Z and could be a great drug candidate for antibiotic development. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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14 pages, 3822 KiB  

Open AccessArticle

Biological Activity of Pulcherrimin from the Meschnikowia pulcherrima Clade

by Dorota Kregiel, Maria Nowacka, Anna Rygala and Renáta Vadkertiová

Molecules 2022, 27(6), 1855; https://doi.org/10.3390/molecules27061855 - 12 Mar 2022

Cited by 21 | Viewed by 3914

Abstract

Pulcherrimin is a secondary metabolite of yeasts belonging to the Metschnikowia pulcherrima clade, and pulcherrimin formation is responsible for the antimicrobial action of its producers. Understanding the environmental function of this metabolite can provide insight into various microbial interactions and enables the efficient [...] Read more.

Pulcherrimin is a secondary metabolite of yeasts belonging to the Metschnikowia pulcherrima clade, and pulcherrimin formation is responsible for the antimicrobial action of its producers. Understanding the environmental function of this metabolite can provide insight into various microbial interactions and enables the efficient development of new effective bioproducts and methods. In this study, we evaluated the antimicrobial and antiadhesive action of yeast pulcherrimin, as well as its protective properties under selected stressful conditions. Classical microbiological plate methods, microscopy, and physico-chemical testing were used. The results show that pure pulcherrimin does not have antimicrobial properties, but its unique hydrophilic nature may hinder the adhesion of hydrophilic bacterial cells to abiotic surfaces. Pulcherrimin also proved to be a good cell protectant against UV–C radiation at both high and low temperatures. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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16 pages, 4843 KiB  

Open AccessArticle

Screening Repurposed Antiviral Small Molecules as Antimycobacterial Compounds by a Lux-Based phoP Promoter-Reporter Platform

by Li Zhu, Annie Wing-Tung Lee, Kelvin Ka-Lok Wu, Peng Gao, Kingsley King-Gee Tam, Rahim Rajwani, Galata Chala Chaburte, Timothy Ting-Leung Ng, Chloe Toi-Mei Chan, Hiu Yin Lao, Wing Cheong Yam, Richard Yi-Tsun Kao and Gilman Kit Hang Siu

Antibiotics 2022, 11(3), 369; https://doi.org/10.3390/antibiotics11030369 - 9 Mar 2022

Cited by 5 | Viewed by 3318

Abstract

The emergence of multidrug-resistant strains and hyper-virulent strains of Mycobacterium tuberculosis are big therapeutic challenges for tuberculosis (TB) control. Repurposing bioactive small-molecule compounds has recently become a new therapeutic approach against TB. This study aimed to identify novel anti-TB agents from a library [...] Read more.

The emergence of multidrug-resistant strains and hyper-virulent strains of Mycobacterium tuberculosis are big therapeutic challenges for tuberculosis (TB) control. Repurposing bioactive small-molecule compounds has recently become a new therapeutic approach against TB. This study aimed to identify novel anti-TB agents from a library of small-molecule compounds via a rapid screening system. A total of 320 small-molecule compounds were used to screen for their ability to suppress the expression of a key virulence gene, phop, of the M. tuberculosis complex using luminescence (lux)-based promoter-reporter platforms. The minimum inhibitory and bactericidal concentrations on drug-resistant M. tuberculosis and cytotoxicity to human macrophages were determined. RNA sequencing (RNA-seq) was conducted to determine the drug mechanisms of the selected compounds as novel antibiotics or anti-virulent agents against the M. tuberculosis complex. The results showed that six compounds displayed bactericidal activity against M. bovis BCG, of which Ebselen demonstrated the lowest cytotoxicity to macrophages and was considered as a potential antibiotic for TB. Another ten compounds did not inhibit the in vitro growth of the M. tuberculosis complex and six of them downregulated the expression of phoP/R significantly. Of these, ST-193 and ST-193 (hydrochloride) showed low cytotoxicity and were suggested to be potential anti-virulence agents for M. tuberculosis. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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20 pages, 2992 KiB  

Open AccessArticle

Synthesis of Novel Tritopic Hydrazone Ligands: Spectroscopy, Biological Activity, DFT, and Molecular Docking Studies

by Sharmin Akther Rupa, Md. Rassel Moni, Md. Abdul Majed Patwary, Md. Mayez Mahmud, Md. Aminul Haque, Jamal Uddin and S. M. Tareque Abedin

Molecules 2022, 27(5), 1656; https://doi.org/10.3390/molecules27051656 - 2 Mar 2022

Cited by 23 | Viewed by 4180

Abstract

Polytopic organic ligands with hydrazone moiety are at the forefront of new drug research among many others due to their unique and versatile functionality and ease of strategic ligand design. Quantum chemical calculations of these polyfunctional ligands can be carried out in silico [...] Read more.

Polytopic organic ligands with hydrazone moiety are at the forefront of new drug research among many others due to their unique and versatile functionality and ease of strategic ligand design. Quantum chemical calculations of these polyfunctional ligands can be carried out in silico to determine the thermodynamic parameters. In this study two new tritopic dihydrazide ligands, N’2, N’6-bis[(1E)-1-(thiophen-2-yl) ethylidene] pyridine-2,6-dicarbohydrazide (L1) and N’2, N’6-bis[(1E)-1-(1H-pyrrol-2-yl) ethylidene] pyridine-2,6-dicarbohydrazide (L2) were successfully prepared by the condensation reaction of pyridine-2,6-dicarboxylic hydrazide with 2-acetylthiophene and 2-acetylpyrrole. The FT-IR, ¹H, and ¹³C NMR, as well as mass spectra of both L1 and L2, were recorded and analyzed. Quantum chemical calculations were performed at the DFT/B3LYP/cc-pvdz/6-311G+(d,p) level of theory to study the molecular geometry, vibrational frequencies, and thermodynamic properties including changes of ∆H, ∆S, and ∆G for both the ligands. The optimized vibrational frequency and (¹H and ¹³C) NMR obtained by B3LYP/cc-pvdz/6-311G+(d,p) showed good agreement with experimental FT-IR and NMR data. Frontier molecular orbital (FMO) calculations were also conducted to find the HOMO, LUMO, and HOMO–LUMO gaps of the two synthesized compounds. To investigate the biological activities of the ligands, L1 and L2 were tested using in vitro bioassays against some Gram-negative and Gram-positive bacteria and fungus strains. In addition, molecular docking was used to study the molecular behavior of L1 and L2 against tyrosinase from Bacillus megaterium. The outcomes revealed that both L1 and L2 can suppress microbial growth of bacteria and fungi with variable potency. The antibacterial activity results demonstrated the compound L2 to be potentially effective against Bacillus megaterium with inhibition zones of 12 mm while the molecular docking study showed the binding energies for L1 and L2 to be −7.7 and −8.8 kcal mol⁻¹, respectively, with tyrosinase from Bacillus megaterium. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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16 pages, 7015 KiB  

Open AccessArticle

Synthesis and Antibacterial Properties of Oligomeric Dehydrogenation Polymer from Lignin Precursors

by Xin Wei, Sheng Cui and Yimin Xie

Molecules 2022, 27(5), 1466; https://doi.org/10.3390/molecules27051466 - 22 Feb 2022

Cited by 11 | Viewed by 2588

Abstract

The lignin precursors of coniferin and syringin were synthesised, and guaiacyl-type and guaiacyl-syringyl-type oligomeric lignin dehydrogenation polymers (DHP and DHP-GS) were prepared with the bulk method. The carbon-13 nuclear magnetic resonance spectroscopy showed that both DHP-G and DHP-GS contained β-O-4, β-5, β-β, β-1, [...] Read more.

The lignin precursors of coniferin and syringin were synthesised, and guaiacyl-type and guaiacyl-syringyl-type oligomeric lignin dehydrogenation polymers (DHP and DHP-GS) were prepared with the bulk method. The carbon-13 nuclear magnetic resonance spectroscopy showed that both DHP-G and DHP-GS contained β-O-4, β-5, β-β, β-1, and 5-5 substructures. Extraction with petroleum ether, ether, ethanol, and acetone resulted in four fractions for each of DHP-G (C₁₁–C₁₄) and DHP-GS (C₂₁–C₂₄). The antibacterial experiments showed that the fractions with lower molecular weight had relatively strong antibacterial activity. The ether-soluble fractions (C₁₂ of DHP-G and C₂₂ of DHP-GS) had strong antibacterial activities against E. coli and S. aureus. The C₁₂ and C₂₂ fractions were further separated by preparative chromatography, and 10 bioactive compounds (G₁–G₅ and GS₁–GS₅) were obtained. The overall antibacterial activities of these 10 compounds was stronger against E. coli than S. aureus. Compounds G₁, G₂, G₃, and GS₁, which had the most significant antibacterial activities, contained β-5 substructures. Of these, G₁ had the best antibacterial activity. Its inhibition zone diameter was 19.81 ± 0.82 mm, and the minimum inhibition concentration was 56.3 ± 6.20 μg/mL. Atmospheric pressure chemical ionisation mass spectrometry (APCI-MS) showed that the antibacterial activity of G₁ was attributable to a phenylcoumarin dimer, while the introduction of syringyl units reduced antibacterial activity. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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16 pages, 1579 KiB  

Open AccessEditor’s ChoiceArticle

Stapling of Peptides Potentiates the Antibiotic Treatment of Acinetobacter baumannii In Vivo

by Gina K. Schouten, Felix M. Paulussen, Oscar P. Kuipers, Wilbert Bitter, Tom N. Grossmann and Peter van Ulsen

Antibiotics 2022, 11(2), 273; https://doi.org/10.3390/antibiotics11020273 - 19 Feb 2022

Cited by 14 | Viewed by 4642

Abstract

The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to [...] Read more.

The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to proteolytic degradation, which greatly limits their clinical potential. One approach to increase stability is to apply a hydrocarbon staple to the antimicrobial peptide, thereby fixing them in an ?-helical conformation, which renders them less exposed to proteolytic activity. In this work we applied several different hydrocarbon staples to two previously described peptides shown to act on the outer membrane, L6 and L8, and tested their activity in a zebrafish embryo infection model using a clinical isolate of Acinetobacter baumannii as a pathogen. We show that the introduction of such a hydrocarbon staple to the peptide L8 improves its in vivo potentiating activity on antibiotic treatment, without increasing its in vivo antimicrobial activity, toxicity or hemolytic activity. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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8 pages, 920 KiB  

Open AccessArticle

Factors Associated with Daptomycin-Induced Eosinophilic Pneumonia

by Kazuhiro Ishikawa, Takahiro Matsuo, Yasumasa Tsuda, Mahbubur Rahman, Yuki Uehara and Nobuyoshi Mori

Antibiotics 2022, 11(2), 254; https://doi.org/10.3390/antibiotics11020254 - 16 Feb 2022

Cited by 3 | Viewed by 2254

Abstract

The risk factors for eosinophilic pneumonia (EP) remain unclear. We investigate the characteristics of patients with daptomycin (DAP)-induced EP and conducted a retrospective observational study. A total of 450 patients aged ≥ 18 years who received DAP (25 DAP with EP, 425 DAP [...] Read more.

The risk factors for eosinophilic pneumonia (EP) remain unclear. We investigate the characteristics of patients with daptomycin (DAP)-induced EP and conducted a retrospective observational study. A total of 450 patients aged ≥ 18 years who received DAP (25 DAP with EP, 425 DAP without EP) were included. The median duration from the first DAP administration to EP onset was 18.0 days. Definite, probable, and possible DAP-induced EP were diagnosed in 0, 9, and 16 patients, respectively. The median age (DAP with EP, 72.0 years; DAP without EP, 64.0 years), DAP dosage/body weight (BW) (9.00 vs. 7.50 mg/kg), blood eosinophil count (cells/μL) (419 vs. 96), and the percentage of hemodialyzed patients (40.0% vs. 13.4%) were significantly higher in patients with EP than in patients without EP in the univariate analysis. In separate multivariate logistic regression analyses, age (odds ratio (OR), 1.03; 95% confidence interval (CI), 1.00–1.05), DAP dosage/BW (OR, 1.61; 95% CI, 1.25–2.07), and hemodialysis (OR, 4.42; 95% CI, 1.86–10.5) were significantly associated with DAP-induced EP. Clinicians may need to consider the potential factors associated with EP, especially in older patients, patients on hemodialysis, or patients who receive > 9.00 mg/kg of DAP. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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17 pages, 21622 KiB  

Open AccessReview

Pharmacological Activities of Soursop (Annona muricata Lin.)

by Mutakin Mutakin, Rizky Fauziati, Fahrina Nur Fadhilah, Ade Zuhrotun, Riezki Amalia and Yuni Elsa Hadisaputri

Molecules 2022, 27(4), 1201; https://doi.org/10.3390/molecules27041201 - 10 Feb 2022

Cited by 61 | Viewed by 22239

Abstract

Soursop (Annona muricata Lin.) is a plant belonging to the Annonaceae family that has been widely used globally as a traditional medicine for many diseases. In this review, we discuss the traditional use, chemical content, and pharmacological activities of A.muricata. From [...] Read more.

Soursop (Annona muricata Lin.) is a plant belonging to the Annonaceae family that has been widely used globally as a traditional medicine for many diseases. In this review, we discuss the traditional use, chemical content, and pharmacological activities of A.muricata. From 49 research articles that were obtained from 1981 to 2021, A.muricata’s activities were shown to include anticancer (25%), antiulcer (17%), antidiabetic (14%), antiprotozoal (10%), antidiarrhea (8%), antibacterial (8%), antiviral (8%), antihypertensive (6%), and wound healing (4%). Several biological activities and the general mechanisms underlying the effects of A.muricata have been tested both in vitro and in vivo. A.muricata contains chemicals such as acetogenins (annomuricins and annonacin), alkaloids (coreximine and reticuline), flavonoids (quercetin), and vitamins, which are predicted to be responsible for the biological activity of A.muricata. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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Open AccessArticle

Preliminary Studies of Antimicrobial Activity of New Synthesized Hybrids of 2-Thiohydantoin and 2-Quinolone Derivatives Activated with Blue Light

by Agnieszka Kania, Waldemar Tejchman, Anna M. Pawlak, Krystian Mokrzyński, Bartosz Różanowski, Bogdan M. Musielak and Magdalena Greczek-Stachura

Molecules 2022, 27(3), 1069; https://doi.org/10.3390/molecules27031069 - 5 Feb 2022

Cited by 28 | Viewed by 2975

Abstract

Thiohydantoin and quinolone derivatives have attracted researchers’ attention because of a broad spectrum of their medical applications. The aim of our research was to synthesize and analyze the antimicrobial properties of novel 2-thiohydantoin and 2-quinolone derivatives. For this purpose, two series of hybrid [...] Read more.

Thiohydantoin and quinolone derivatives have attracted researchers’ attention because of a broad spectrum of their medical applications. The aim of our research was to synthesize and analyze the antimicrobial properties of novel 2-thiohydantoin and 2-quinolone derivatives. For this purpose, two series of hybrid compounds were synthesized. Both series consisted of 2-thiohydantoin core and 2-quinolone derivative ring, however one of them was enriched with an acetic acid group at N3 atom in 2-thiohydantoin core. Antibacterial properties of these compounds were examined against bacteria: Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. The antimicrobial assay was carried out using a serial dilution method to obtain the MIC. The influence of blue light irradiation on the tested compounds was investigated. The relative yield of singlet oxygen (¹O₂*, ¹Δ_g) generation upon excitation with 420 nm was determined by a comparative method, employing perinaphthenone (PN) as a standard. Antimicrobial properties were also investigated after blue light irradiation of the suspensions of the hybrids and bacteria placed in microtitrate plates. Preliminary results confirmed that some of the hybrid compounds showed bacteriostatic activity to the reference Gram-positive bacterial strains and a few of them were bacteriostatic towards Gram-negative bacteria, as well. Blue light activation enhanced bacteriostatic effect of the tested compounds. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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Open AccessArticle

Antileishmanial Effects of Acetylene Acetogenins from Seeds of Porcelia macrocarpa (Warm.) R.E. Fries (Annonaceae) and Semisynthetic Derivatives

by Ivanildo A. Brito, Fernanda Thevenard, Thais A. Costa-Silva, Samuel S. Oliveira, Rodrigo L. O. R. Cunha, Emerson A. de Oliveira, Patricia Sartorelli, Rafael C. Guadagnin, Maiara M. Romanelli, Andre G. Tempone and João Henrique G. Lago

Molecules 2022, 27(3), 893; https://doi.org/10.3390/molecules27030893 - 28 Jan 2022

Cited by 4 | Viewed by 2376

Abstract

As part of our continuous studies involving the prospection of natural products from Brazilian flora aiming at the discovery of prototypes for the development of new antiparasitic drugs, the present study describes the isolation of two natural acetylene acetogenins, (2S,3R [...] Read more.

As part of our continuous studies involving the prospection of natural products from Brazilian flora aiming at the discovery of prototypes for the development of new antiparasitic drugs, the present study describes the isolation of two natural acetylene acetogenins, (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-eicos-11′-yn-19′-enyl)butanolide (1) and (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-eicos-11′-ynyl)butanolide (2), from the seeds of Porcelia macrocarpa (Warm.) R.E. Fries (Annonaceae). Using an ex-vivo assay, compound 1 showed an IC₅₀ value of 29.9 μM against the intracellular amastigote forms of Leishmania (L.) infantum, whereas compound 2 was inactive. These results suggested that the terminal double bond plays an important role in the activity. This effect was also observed for the semisynthetic acetylated (1a and 2a) and eliminated (1b and 2b) derivatives, since only compounds containing a double bond at C-19 displayed activity, resulting in IC₅₀ values of 43.3 μM (1a) and 23.1 μM (1b). In order to evaluate the effect of the triple bond in the antileishmanial potential, the mixture of compounds 1 + 2 was subjected to catalytic hydrogenation to afford a compound 3 containing a saturated side chain. The antiparasitic assays performed with compound 3, acetylated (3a), and eliminated (3b) derivatives confirmed the lack of activity. Furthermore, an in-silico study using the SwissADME online platform was performed to bioactive compounds 1, 1a, and 1b in order to investigate their physicochemical parameters, pharmacokinetics, and drug-likeness. Despite the reduced effect against amastigote forms of the parasite to the purified compounds, different mixtures of compounds 1 + 2, 1a + 2a, and 1b + 2b were prepared and exhibited IC₅₀ values ranging from 7.9 to 38.4 μM, with no toxicity for NCTC mammalian cells (CC₅₀ > 200 μM). Selectivity indexes to these mixtures ranged from >5.2 to >25.3. The obtained results indicate that seeds of Porcelia macrocarpa are a promising source of interesting prototypes for further modifications aiming at the discovery of new antileishmanial drugs. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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Open AccessArticle

The Chemical Property Position of Bedaquiline Construed by a Chemical Global Positioning System-Natural Product

by Muaaz Mutaz Alajlani

Molecules 2022, 27(3), 753; https://doi.org/10.3390/molecules27030753 - 24 Jan 2022

Cited by 5 | Viewed by 3453

Abstract

Bedaquiline is a novel adenosine triphosphate synthase inhibitor anti-tuberculosis drug. Bedaquiline belongs to the class of diarylquinolines, which are antituberculosis drugs that are quite different mechanistically from quinolines and flouroquinolines. The fact that relatively similar chemical drugs produce different mechanisms of action is [...] Read more.

Bedaquiline is a novel adenosine triphosphate synthase inhibitor anti-tuberculosis drug. Bedaquiline belongs to the class of diarylquinolines, which are antituberculosis drugs that are quite different mechanistically from quinolines and flouroquinolines. The fact that relatively similar chemical drugs produce different mechanisms of action is still not widely understood. To enhance discrimination in favor of bedaquiline, a new approach using eight-score principal component analysis (PCA), provided by a ChemGPS-NP model, is proposed. PCA scores were calculated based on 35 + 1 different physicochemical properties and demonstrated clear differences when compared with other quinolines. The ChemGPS-NP model provided an exceptional 100 compounds nearest to bedaquiline from antituberculosis screening sets (with a cumulative Euclidian distance of 196.83), compared with the different 2Dsimilarity provided by Tanimoto methods (extended connective fingerprints and the Molecular ACCess System, showing 30% and 182% increases in cumulative Euclidian distance, respectively). Potentially similar compounds from publicly available antituberculosis compounds and Maybridge sets, based on bedaquiline’s eight-dimensional similarity and different filtrations, were identified too. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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Open AccessArticle

In Silico Drug Repurposing Approach: Investigation of Mycobacterium tuberculosis FadD32 Targeted by FDA-Approved Drugs

by Nolwazi Thobeka Portia Ngidi, Kgothatso Eugene Machaba and Ndumiso Nhlakanipho Mhlongo

Molecules 2022, 27(3), 668; https://doi.org/10.3390/molecules27030668 - 20 Jan 2022

Cited by 11 | Viewed by 3313

Abstract

Background: Despite the enormous efforts made towards combating tuberculosis (TB), the disease remains a major global threat. Hence, new drugs with novel mechanisms against TB are urgently needed. Fatty acid degradation protein D32 (FadD32) has been identified as a promising drug target [...] Read more.

Background: Despite the enormous efforts made towards combating tuberculosis (TB), the disease remains a major global threat. Hence, new drugs with novel mechanisms against TB are urgently needed. Fatty acid degradation protein D32 (FadD32) has been identified as a promising drug target against TB, the protein is required for the biosynthesis of mycolic acids, hence, essential for the growth and multiplication of the mycobacterium. However, the FadD32 mechanism upon the binding of FDA-approved drugs is not well established. Herein, we applied virtual screening (VS), molecular docking, and molecular dynamic (MD) simulation to identify potential FDA-approved drugs against FadD32. Methodology/Results: VS technique was found promising to identify four FDA-approved drugs (accolate, sorafenib, mefloquine, and loperamide) with higher molecular docking scores, ranging from −8.0 to −10.0 kcal/mol. Post-MD analysis showed that the accolate hit displayed the highest total binding energy of −45.13 kcal/mol. Results also showed that the accolate hit formed more interactions with FadD32 active site residues and all active site residues displayed an increase in total binding contribution. RMSD, RMSF, Rg, and DCCM analysis further supported that the presence of accolate exhibited more structural stability, lower bimolecular flexibility, and more compactness into the FadD32 protein. Conclusions: Our study revealed accolate as the best potential drug against FadD32, hence a prospective anti-TB drug in TB therapy. In addition, we believe that the approach presented in the current study will serve as a cornerstone to identifying new potential inhibitors against a wide range of biological targets. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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Open AccessArticle

Comparative Transcriptome Analysis Reveals Differentially Expressed Genes Related to Antimicrobial Properties of Lysostaphin in Staphylococcus aureus

by Xianghe Yan, Yanping Xie, Charles Li, David M. Donovan, Andrew Gehring, Peter Irwin and Yiping He

Antibiotics 2022, 11(2), 125; https://doi.org/10.3390/antibiotics11020125 - 18 Jan 2022

Cited by 3 | Viewed by 3385

Abstract

Comparative transcriptome analysis and de novo short-read assembly of S. aureus Newman strains revealed significant transcriptional changes in response to the exposure to triple-acting staphylolytic peptidoglycan hydrolase (PGH) 1801. Most altered transcriptions were associated with the membrane, cell wall, and related genes, including [...] Read more.

Comparative transcriptome analysis and de novo short-read assembly of S. aureus Newman strains revealed significant transcriptional changes in response to the exposure to triple-acting staphylolytic peptidoglycan hydrolase (PGH) 1801. Most altered transcriptions were associated with the membrane, cell wall, and related genes, including amidase, peptidase, holin, and phospholipase D/transphosphatidylase. The differential expression of genes obtained from RNA-seq was confirmed by reverse transcription quantitative PCR. Moreover, some of these gene expression changes were consistent with the observed structural perturbations at the DNA and RNA levels. These structural changes in the genes encoding membrane/cell surface proteins and altered gene expressions are the candidates for resistance to these novel antimicrobials. The findings in this study could provide insight into the design of new antimicrobial agents. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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17 pages, 2476 KiB  

Open AccessArticle

In Vitro Evaluation of the Cytotoxic Effect of Streptococcus pyogenes Strains, Protegrin PG-1, Cathelicidin LL-37, Nerve Growth Factor and Chemotherapy on the C6 Glioma Cell Line

by Alexandr N. Chernov, Anna Tsapieva, Diana A. Alaverdian, Tatiana A. Filatenkova, Elvira S. Galimova, Mariia Suvorova, Olga V. Shamova and Alexander N. Suvorov

Molecules 2022, 27(2), 569; https://doi.org/10.3390/molecules27020569 - 17 Jan 2022

Cited by 9 | Viewed by 3289

Abstract

Brain cancer treatment, where glioblastoma represents up to 50% of all CNS malignancies, is one of the most challenging calls for neurooncologists. The major driver of this study was a search for new approaches for the treatment of glioblastoma. We tested live S. [...] Read more.

Brain cancer treatment, where glioblastoma represents up to 50% of all CNS malignancies, is one of the most challenging calls for neurooncologists. The major driver of this study was a search for new approaches for the treatment of glioblastoma. We tested live S. pyogenes, cathelicidin family peptides and NGF, assessing the oncolytic activity of these compounds as monotherapy or in combination with chemotherapeutics. For cytotoxicity evaluation, we used the MTT assay, trypan blue assay and the xCELLigence system. To evaluate the safety of the studied therapeutic approaches, we performed experiments on normal human fibroblasts. Streptococci and peptides demonstrated high antitumor efficiency against glioma C6 cells in all assays applied, surpassing the effect of chemotherapeutics (doxorubicin, carboplatin, cisplatin, etoposide). A real-time cytotoxicity analysis showed that the cell viability index dropped to 21% 2–5 h after S. pyogenes strain exposure. It was shown that LL-37, PG-1 and NGF also exhibited strong antitumor effects on C6 glioma cells when applied at less than 10⁻⁴ M. Synergistic effects for combinations of PG-1 with carboplatin and LL-37 with etoposide were shown. Combinations of S. pyogenes strain #7 with NGF or LL-37 demonstrated a cytotoxic effect (56.7% and 57.3%, accordingly) on C6 glioma cells after 3 h of exposure. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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Open AccessArticle

In Silico and In Vitro Structure–Activity Relationship of Mastoparan and Its Analogs

by Prapenpuksiri Rungsa, Steve Peigneur, Nisachon Jangpromma, Sompong Klaynongsruang, Jan Tytgat and Sakda Daduang

Molecules 2022, 27(2), 561; https://doi.org/10.3390/molecules27020561 - 16 Jan 2022

Cited by 11 | Viewed by 3111

Abstract

Antimicrobial peptides are an important class of therapeutic agent used against a wide range of pathogens such as Gram-negative and Gram-positive bacteria, fungi, and viruses. Mastoparan (MpVT) is an α-helix and amphipathic tetradecapeptide obtained from Vespa tropica venom. This peptide exhibits antibacterial activity. [...] Read more.

Antimicrobial peptides are an important class of therapeutic agent used against a wide range of pathogens such as Gram-negative and Gram-positive bacteria, fungi, and viruses. Mastoparan (MpVT) is an α-helix and amphipathic tetradecapeptide obtained from Vespa tropica venom. This peptide exhibits antibacterial activity. In this work, we investigate the effect of amino acid substitutions and deletion of the first three C-terminal residues on the structure–activity relationship. In this in silico study, the predicted structure of MpVT and its analog have characteristic features of linear cationic peptides rich in hydrophobic and basic amino acids without disulfide bonds. The secondary structure and the biological activity of six designed analogs are studied. The biological activity assays show that the substitution of phenylalanine (MpVT1) results in a higher antibacterial activity than that of MpVT without increasing toxicity. The analogs with the first three deleted C-terminal residues showed decreased antibacterial and hemolytic activity. The CD (circular dichroism) spectra of these peptides show a high content α-helical conformation in the presence of 40% 2,2,2-trifluoroethanol (TFE). In conclusion, the first three C-terminal deletions reduced the length of the α-helix, explaining the decreased biological activity. MpVTs show that the hemolytic activity of mastoparan is correlated to mean hydrophobicity and mean hydrophobic moment. The position and spatial arrangement of specific hydrophobic residues on the non-polar face of α-helical AMPs may be crucial for the interaction of AMPs with cell membranes. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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Open AccessArticle

Development of New Antimicrobial Oleanonic Acid Polyamine Conjugates

by Elmira F. Khusnutdinova, Véronique Sinou, Denis A. Babkov, Oxana Kazakova and Jean Michel Brunel

Antibiotics 2022, 11(1), 94; https://doi.org/10.3390/antibiotics11010094 - 12 Jan 2022

Cited by 12 | Viewed by 2612

Abstract

A series of oleanolic acid derivatives holding oxo- or 3-N-polyamino-3-deoxy-substituents at C3 as well as carboxamide function at C17 with different long chain polyamines have been synthesized and evaluated for antimicrobial activities. Almost all series presented good to moderate activity against [...] Read more.

A series of oleanolic acid derivatives holding oxo- or 3-N-polyamino-3-deoxy-substituents at C3 as well as carboxamide function at C17 with different long chain polyamines have been synthesized and evaluated for antimicrobial activities. Almost all series presented good to moderate activity against Gram-positive S. aureus, S. faecalis and B. cereus bacteria with minimum inhibitory concentration (MIC) values from 3.125 to 200 µg/mL. Moreover, compounds possess important antimicrobial activities against Gram-negative E. coli, P. aeruginosa, S. enterica, and EA289 bacteria with MICs ranging from 6.25 to 200 µg/mL. The testing of ability to restore antibiotic activity of doxycycline and erythromycin at a 2 µg/mL concentration in a synergistic assay showed that oleanonic acid conjugate with spermine spacered through propargylamide led to a moderate improvement in terms of antimicrobial activities of the different selected combinations against both P. aeruginosa and E. coli. The study of mechanism of action of the lead conjugate 2i presenting a N-methyl norspermidine moiety showed the effect of disruption of the outer bacterial membrane of P. aeruginosa PA01 cells. Computational ADMET profiling renders this compound as a suitable starting point for pharmacokinetic optimization. These results give confidence to the successful outcome of bioconjugation of polyamines and oleanane-type triterpenoids in the development of antimicrobial agents. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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16 pages, 3558 KiB  

Open AccessArticle

Impact of a Novel Anticoccidial Analogue on Systemic Staphylococcus aureus Infection in a Bioluminescent Mouse Model

by Hang Thi Nguyen, Henrietta Venter, Lucy Woolford, Kelly Young, Adam McCluskey, Sanjay Garg, Stephen W. Page, Darren J. Trott and Abiodun David Ogunniyi

Antibiotics 2022, 11(1), 65; https://doi.org/10.3390/antibiotics11010065 - 6 Jan 2022

Cited by 2 | Viewed by 3225

Abstract

In this study, we investigated the potential of an analogue of robenidine (NCL179) to expand its chemical diversity for the treatment of multidrug-resistant (MDR) bacterial infections. We show that NCL179 exhibits potent bactericidal activity, returning minimum inhibitory concentration/minimum bactericidal concentrations (MICs/MBCs) of 1–2 [...] Read more.

In this study, we investigated the potential of an analogue of robenidine (NCL179) to expand its chemical diversity for the treatment of multidrug-resistant (MDR) bacterial infections. We show that NCL179 exhibits potent bactericidal activity, returning minimum inhibitory concentration/minimum bactericidal concentrations (MICs/MBCs) of 1–2 µg/mL against methicillin-resistant Staphylococcus aureus, MICs/MBCs of 1–2 µg/mL against methicillin-resistant S. pseudintermedius and MICs/MBCs of 2–4 µg/mL against vancomycin-resistant enterococci. NCL179 showed synergistic activity against clinical isolates and reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in the presence of sub-inhibitory concentrations of colistin, whereas NCL179 alone had no activity. Mice given oral NCL179 at 10 mg/kg and 50 mg/kg (4 × doses, 4 h apart) showed no adverse clinical effects and no observable histological effects in any of the organs examined. In a bioluminescent S. aureus sepsis challenge model, mice that received four oral doses of NCL179 at 50 mg/kg at 4 h intervals exhibited significantly reduced bacterial loads, longer survival times and higher overall survival rates than the vehicle-only treated mice. These results support NCL179 as a valid candidate for further development to treat MDR bacterial infections as a stand-alone antibiotic or in combination with existing antibiotic classes. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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Open AccessArticle

Solvent-Free Synthesis, In Vitro and In Silico Studies of Novel Potential 1,3,4-Thiadiazole-Based Molecules against Microbial Pathogens

by Ihsan A. Shehadi, Mohamad T. Abdelrahman, Mohamed Abdelraof and Huda R. M. Rashdan

Molecules 2022, 27(2), 342; https://doi.org/10.3390/molecules27020342 - 6 Jan 2022

Cited by 21 | Viewed by 2746

Abstract

A new series of 1,3,4-thiadiazoles was synthesized by the reaction of methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate (2) with selected derivatives of hydrazonoyl halide by grinding method at room temperature. The chemical structures of the newly synthesized derivatives were resolved from correct spectral and [...] Read more.

A new series of 1,3,4-thiadiazoles was synthesized by the reaction of methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate (2) with selected derivatives of hydrazonoyl halide by grinding method at room temperature. The chemical structures of the newly synthesized derivatives were resolved from correct spectral and microanalytical data. Moreover, all synthesized compounds were screened for their antimicrobial activities using Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Bacillus subtilis, Staphylococcus aureus, and Candida albicans. However, compounds 3 and 5 showed significant antimicrobial activity against all tested microorganisms. The other prepared compounds exhibited either only antimicrobial activity against Gram-positive bacteria like compounds 4 and 6, or only antifungal activity like compound 7. A molecular docking study of the compounds was performed against two important microbial enzymes: tyrosyl-tRNA synthetase (TyrRS) and N-myristoyl transferase (Nmt). The tested compounds showed variety in binding poses and interactions. However, compound 3 showed the best interactions in terms of number of hydrogen bonds, and the lowest affinity binding energy (−8.4 and −9.1 kcal/mol, respectively). From the in vitro and in silico studies, compound 3 is a good candidate for the next steps of the drug development process as an antimicrobial drug. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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Open AccessArticle

Dictamnine Inhibits the Adhesion to and Invasion of Uropathogenic Escherichia Coli (UPEC) to Urothelial Cells

by Wenbo Yang, Peng Liu, Ying Chen, Qingyu Lv, Zhongtian Wang, Wenhua Huang, Hua Jiang, Yuling Zheng, Yongqiang Jiang and Liping Sun

Molecules 2022, 27(1), 272; https://doi.org/10.3390/molecules27010272 - 2 Jan 2022

Cited by 14 | Viewed by 3228

Abstract

Uropathogenic Escherichia coli (UPEC) is the most common pathogenic bacteria associated with urinary tract infection (UTI). UPEC can cause UTI by adhering to and invading uroepithelial cells. Fimbriae is the most important virulence factor of UPEC, and a potentially promising target in developing [...] Read more.

Uropathogenic Escherichia coli (UPEC) is the most common pathogenic bacteria associated with urinary tract infection (UTI). UPEC can cause UTI by adhering to and invading uroepithelial cells. Fimbriae is the most important virulence factor of UPEC, and a potentially promising target in developing novel antibacterial treatments. In this study, the antibacterial properties and effects of the compound dictamnine, extracted from the traditional Chinese medicine Cortex Dictamni, on the bacterial morphology, cell adhesion, and invasion of UPEC were studied. Dictamnine exhibited no obvious antibacterial activity against UPEC, but significantly impeded the ability of UPEC to adhere to and invade uroepithelial cells. RT-qPCR analysis showed that treatment downregulated the expression of type 1 fimbriae, P fimbriae, and curli fimbriae adhesion genes, and also downregulated adhesion-related receptor genes of uroepithelial cells. Transmission electron microscopy showed that dictamnine destroyed the structure of the fimbriae and the surface of the bacteria became smooth. These results suggest that dictamnine may help to prevent UTI by simultaneously targeting UPEC fimbriae and urothelial adhesin receptors, and may have a potential use as a new anti-UPEC drug. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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Open AccessArticle

Lacticaseicin 30 and Colistin as a Promising Antibiotic Formulation against Gram-Negative β-Lactamase-Producing Strains and Colistin-Resistant Strains

by Désiré Madi-Moussa, Yanath Belguesmia, Audrey Charlet, Djamel Drider and Françoise Coucheney

Antibiotics 2022, 11(1), 20; https://doi.org/10.3390/antibiotics11010020 - 24 Dec 2021

Cited by 6 | Viewed by 3148

Abstract

Antimicrobial resistance is a global health concern across the world and it is foreseen to swell if no actions are taken now. To help curbing this well announced crisis different strategies are announced, and these include the use of antimicrobial peptides (AMP), which [...] Read more.

Antimicrobial resistance is a global health concern across the world and it is foreseen to swell if no actions are taken now. To help curbing this well announced crisis different strategies are announced, and these include the use of antimicrobial peptides (AMP), which are remarkable molecules known for their killing activities towards pathogenic bacteria. Bacteriocins are ribosomally synthesized AMP produced by almost all prokaryotic lineages. Bacteriocins, unlike antibiotics, offer a set of advantages in terms of cytotoxicity towards eukaryotic cells, their mode of action, cross-resistance and impact of microbiota content. Most known bacteriocins are produced by Gram-positive bacteria, and specifically by lactic acid bacteria (LAB). LAB-bacteriocins were steadily reported and characterized for their activity against genetically related Gram-positive bacteria, and seldom against Gram-negative bacteria. The aim of this study is to show that lacticaseicin 30, which is one of the bacteriocins produced by Lacticaseibacillus paracasei CNCM I-5369, is active against Gram-negative clinical strains (Salmonella enterica Enteritidis H10, S. enterica Typhimurium H97, Enterobacter cloacae H51, Escherichia coli H45, E. coli H51, E. coli H66, Klebsiella oxytoca H40, K. pneumoniae H71, K. variicola H77, K. pneumoniae H79, K. pneumoniae H79), whereas antibiotics failed. In addition, lacticaseicin 30 and colistin enabled synergistic interactions towards the aforementioned target Gram-negative clinical strains. Further, the combinations of lacticaseicin 30 and colistin prompted a drastic downregulation of mcr-1 and mcr-9 genes, which are associated with the colistin resistance phenotypes of these clinical strains. This report shows that lacticaseicin 30 is active against Gram-negative clinical strains carrying a rainbow of mcr genes, and the combination of these antimicrobials constitutes a promising therapeutic option that needs to be further exploited. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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10 pages, 1237 KiB  

Open AccessArticle

Evaluation of the Antiviral Activity against Infectious Pancreatic Necrosis Virus (IPNV) of a Copper (I) Homoleptic Complex with a Coumarin as Ligand

by Daniela Gutiérrez, Almendra Benavides, Beatriz Valenzuela, Carolina Mascayano, Maialen Aldabaldetrecu, Angel Olguín, Juan Guerrero and Brenda Modak

Molecules 2022, 27(1), 32; https://doi.org/10.3390/molecules27010032 - 22 Dec 2021

Cited by 8 | Viewed by 2826

Abstract

The aquatic infectious pancreatic necrosis virus (IPNV) causes a severe disease in farmed salmonid fish that generates great economic losses in the aquaculture industry. In the search for new tools to control the disease, in this paper we show the results obtained from [...] Read more.

The aquatic infectious pancreatic necrosis virus (IPNV) causes a severe disease in farmed salmonid fish that generates great economic losses in the aquaculture industry. In the search for new tools to control the disease, in this paper we show the results obtained from the evaluation of the antiviral effect of [Cu(NN₁)₂](ClO₄) Cu(I) complex, synthesized in our laboratory, where the NN₁ ligand is a synthetic derivate of the natural compound coumarin. This complex demonstrated antiviral activity against IPNV at 5.0 and 15.0 µg/mL causing a decrease viral load 99.0% and 99.5%, respectively. The Molecular Docking studies carried out showed that the copper complex would interact with the VP2 protein, specifically in the S domain, altering the process of entry of the virus into the host cell. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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12 pages, 3717 KiB  

Open AccessArticle

Suppressing Alpha-Hemolysin as Potential Target to Screen of Flavonoids to Combat Bacterial Coinfection

by Shangwen He, Qian Deng, Bingbing Liang, Feike Yu, Xiaohan Yu, Dawei Guo, Xiaoye Liu and Hong Dong

Molecules 2021, 26(24), 7577; https://doi.org/10.3390/molecules26247577 - 14 Dec 2021

Cited by 9 | Viewed by 3040

Abstract

The rapid emergence of bacterial coinfection caused by cytosolic bacteria has become a huge threat to public health worldwide. Past efforts have been devoted to discover the broad-spectrum antibiotics, while the emergence of antibiotic resistance encourages the development of antibacterial agents. In essence, [...] Read more.

The rapid emergence of bacterial coinfection caused by cytosolic bacteria has become a huge threat to public health worldwide. Past efforts have been devoted to discover the broad-spectrum antibiotics, while the emergence of antibiotic resistance encourages the development of antibacterial agents. In essence, bacterial virulence is a factor in antibiotic tolerance. However, the discovery and development of new antibacterial drugs and special antitoxin drugs is much more difficult in the antibiotic resistance era. Herein, we hypothesize that antitoxin hemolytic activity can serve as a screening principle to select antibacterial drugs to combat coinfection from natural products. Being the most abundant natural drug of plant origins, flavonoids were selected to assess the ability of antibacterial coinfections in this paper. Firstly, we note that four flavonoids, namely, baicalin, catechin, kaempferol, and quercetin, have previously exhibited antibacterial abilities. Then, we found that baicalin, kaempferol, and quercetin have better inhibitions of hemolytic activity of Hla than catechin. In addition, kaempferol and quercetin, have therapeutic effectivity for the coinfections of Staphylococcus aureus and Pseudomonas aeruginosa in vitro and in vivo. Finally, our results indicated that kaempferol and quercetin therapied the bacterial coinfection by inhibiting S. aureus α-hemolysin (Hla) and reduced the host inflammatory response. These results suggest that antitoxins may play a promising role as a potential target for screening flavonoids to combat bacterial coinfection. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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31 pages, 3229 KiB  

Open AccessReview

Potential Therapeutic Targets for Combination Antibody Therapy against Pseudomonas aeruginosa Infections

by Luke L. Proctor, Whitney L. Ward, Conner S. Roggy, Alexandra G. Koontz, Katie M. Clark, Alyssa P. Quinn, Meredith Schroeder, Amanda E. Brooks, James M. Small, Francina D. Towne and Benjamin D. Brooks

Antibiotics 2021, 10(12), 1530; https://doi.org/10.3390/antibiotics10121530 - 14 Dec 2021

Cited by 13 | Viewed by 12164

Abstract

Despite advances in antimicrobial therapy and even the advent of some effective vaccines, Pseudomonas aeruginosa (P. aeruginosa) remains a significant cause of infectious disease, primarily due to antibiotic resistance. Although P. aeruginosa is commonly treatable with readily available therapeutics, these therapies are not [...] Read more.

Despite advances in antimicrobial therapy and even the advent of some effective vaccines, Pseudomonas aeruginosa (P. aeruginosa) remains a significant cause of infectious disease, primarily due to antibiotic resistance. Although P. aeruginosa is commonly treatable with readily available therapeutics, these therapies are not always efficacious, particularly for certain classes of patients (e.g., cystic fibrosis (CF)) and for drug-resistant strains. Multi-drug resistant P. aeruginosa infections are listed on both the CDC’s and WHO’s list of serious worldwide threats. This increasing emergence of drug resistance and prevalence of P. aeruginosa highlights the need to identify new therapeutic strategies. Combinations of monoclonal antibodies against different targets and epitopes have demonstrated synergistic efficacy with each other as well as in combination with antimicrobial agents typically used to treat these infections. Such a strategy has reduced the ability of infectious agents to develop resistance. This manuscript details the development of potential therapeutic targets for polyclonal antibody therapies to combat the emergence of multidrug-resistant P. aeruginosa infections. In particular, potential drug targets for combinational immunotherapy against P. aeruginosa are identified to combat current and future drug resistance. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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17 pages, 1958 KiB  

Open AccessReview

How to Combat Gram-Negative Bacteria Using Antimicrobial Peptides: A Challenge or an Unattainable Goal?

by Adriana Barreto-Santamaría, Gabriela Arévalo-Pinzón, Manuel A. Patarroyo and Manuel E. Patarroyo

Antibiotics 2021, 10(12), 1499; https://doi.org/10.3390/antibiotics10121499 - 7 Dec 2021

Cited by 28 | Viewed by 6309

Abstract

Antimicrobial peptides (AMPs) represent a promising and effective alternative for combating pathogens, having some advantages compared to conventional antibiotics. However, AMPs must also contend with complex and specialised Gram-negative bacteria envelops. The variety of lipopolysaccharide and phospholipid composition in Gram-negative bacteria strains and [...] Read more.

Antimicrobial peptides (AMPs) represent a promising and effective alternative for combating pathogens, having some advantages compared to conventional antibiotics. However, AMPs must also contend with complex and specialised Gram-negative bacteria envelops. The variety of lipopolysaccharide and phospholipid composition in Gram-negative bacteria strains and species are decisive characteristics regarding their susceptibility or resistance to AMPs. Such biological and structural barriers have created delays in tuning AMPs to deal with Gram-negative bacteria. This becomes even more acute because little is known about the interaction AMP–Gram-negative bacteria and/or AMPs’ physicochemical characteristics, which could lead to obtaining selective molecules against Gram-negative bacteria. As a consequence, available AMPs usually have highly associated haemolytic and/or cytotoxic activity. Only one AMP has so far been FDA approved and another two are currently in clinical trials against Gram-negative bacteria. Such a pessimistic panorama suggests that efforts should be concentrated on the search for new molecules, designs and strategies for combating infection caused by this type of microorganism. This review has therefore been aimed at describing the currently available AMPs for combating Gram-negative bacteria, exploring the characteristics of these bacteria’s cell envelop hampering the development of new AMPs, and offers a perspective regarding the challenges for designing new AMPs against Gram-negative bacteria. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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7 pages, 992 KiB  

Open AccessCommunication

Assessment of the Antibacterial Efficacy of Halicin against Pathogenic Bacteria

by Rayan Y. Booq, Essam A. Tawfik, Haya A. Alfassam, Ahmed J. Alfahad and Essam J. Alyamani

Antibiotics 2021, 10(12), 1480; https://doi.org/10.3390/antibiotics10121480 - 2 Dec 2021

Cited by 18 | Viewed by 4886

Abstract

Artificial intelligence (AI) is a new technology that has been employed to screen and discover new drugs. Using AI, an anti-diabetic treatment (Halicin) was nominated and proven to have a unique antibacterial activity against several harmful bacterial strains, including multidrug-resistant bacteria. This study [...] Read more.

Artificial intelligence (AI) is a new technology that has been employed to screen and discover new drugs. Using AI, an anti-diabetic treatment (Halicin) was nominated and proven to have a unique antibacterial activity against several harmful bacterial strains, including multidrug-resistant bacteria. This study aims to explore the antibacterial effect of halicin and microbial susceptibility using the zone of inhibition and the minimum inhibition concentration (MIC) values while assessing the stability of stored halicin over a period of time with cost-effective and straightforward methods. Linear regression graphs were constructed, and the correlation coefficient was calculated. The new antibacterial agent was able to inhibit all tested gram-positive and gram-negative bacterial strains, but in different concentrations—including the A. baumannii multidrug-resistant (MDR) isolate. The MIC of halicin was found to be 16 μg/mL for S. aureus (ATCC BAA-977), 32 μg/mL for E. coli (ATCC 25922), 128 μg/mL for A. baumannii (ATCC BAA-747), and 256 μg/mL for MDR A. baumannii. Upon storage, the MICs were increased, suggesting instability of the drug after approximately a week of storage at 4 °C. MICs and zones of inhibition were found to be high (R = 0.90 to 0.98), suggesting that halicin has a promising antimicrobial activity and may be used as a wide-spectrum antibacterial drug. However, the drug’s pharmacokinetics have not been investigated, and further elucidation is needed. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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13 pages, 2803 KiB  

Open AccessArticle

Transporter Protein-Guided Genome Mining for Head-to-Tail Cyclized Bacteriocins

by Daniel Major, Lara Flanzbaum, Leah Lussier, Carly Davies, Kristian Mark P. Caldo and Jeella Z. Acedo

Molecules 2021, 26(23), 7218; https://doi.org/10.3390/molecules26237218 - 28 Nov 2021

Cited by 13 | Viewed by 3150

Abstract

Head-to-tail cyclized bacteriocins are ribosomally synthesized antimicrobial peptides that are defined by peptide backbone cyclization involving the N- and C- terminal amino acids. Their cyclic nature and overall three-dimensional fold confer superior stability against extreme pH and temperature conditions, and protease degradation. Most [...] Read more.

Head-to-tail cyclized bacteriocins are ribosomally synthesized antimicrobial peptides that are defined by peptide backbone cyclization involving the N- and C- terminal amino acids. Their cyclic nature and overall three-dimensional fold confer superior stability against extreme pH and temperature conditions, and protease degradation. Most of the characterized head-to-tail cyclized bacteriocins were discovered through a traditional approach that involved the screening of bacterial isolates for antimicrobial activity and subsequent isolation and characterization of the active molecule. In this study, we performed genome mining using transporter protein sequences associated with experimentally validated head-to-tail cyclized bacteriocins as driver sequences to search for novel bacteriocins. Biosynthetic gene cluster analysis was then performed to select the high probability functional gene clusters. A total of 387 producer strains that encode putative head-to-tail cyclized bacteriocins were identified. Sequence and phylogenetic analyses revealed that this class of bacteriocins is more diverse than previously thought. Furthermore, our genome mining strategy captured hits that were not identified in precursor-based bioprospecting, showcasing the utility of this approach to expanding the repertoire of head-to-tail cyclized bacteriocins. This work sets the stage for future isolation of novel head-to-tail cyclized bacteriocins to serve as possible alternatives to traditional antibiotics and potentially help address the increasing threat posed by resistant pathogens. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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32 pages, 16513 KiB  

Open AccessReview

Antimicrobial and Antiviral (SARS-CoV-2) Potential of Cannabinoids and Cannabis sativa: A Comprehensive Review

by Md Sultan Mahmud, Mohammad Sorowar Hossain, A. T. M. Faiz Ahmed, Md Zahidul Islam, Md Emdad Sarker and Md Reajul Islam

Molecules 2021, 26(23), 7216; https://doi.org/10.3390/molecules26237216 - 28 Nov 2021

Cited by 25 | Viewed by 9689

Abstract

Antimicrobial resistance has emerged as a global health crisis and, therefore, new drug discovery is a paramount need. Cannabis sativa contains hundreds of chemical constituents produced by secondary metabolism, exerting outstanding antimicrobial, antiviral, and therapeutic properties. This paper comprehensively reviews the antimicrobial and [...] Read more.

Antimicrobial resistance has emerged as a global health crisis and, therefore, new drug discovery is a paramount need. Cannabis sativa contains hundreds of chemical constituents produced by secondary metabolism, exerting outstanding antimicrobial, antiviral, and therapeutic properties. This paper comprehensively reviews the antimicrobial and antiviral (particularly against SARS-CoV-2) properties of C. sativa with the potential for new antibiotic drug and/or natural antimicrobial agents for industrial or agricultural use, and their therapeutic potential against the newly emerged coronavirus disease (COVID-19). Cannabis compounds have good potential as drug candidates for new antibiotics, even for some of the WHO’s current priority list of resistant pathogens. Recent studies revealed that cannabinoids seem to have stable conformations with the binding pocket of the M^pro enzyme of SARS-CoV-2, which has a pivotal role in viral replication and transcription. They are found to be suppressive of viral entry and viral activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in the host cellular system. The therapeutic potential of cannabinoids as anti-inflammatory compounds is hypothesized for the treatment of COVID-19. However, more systemic investigations are warranted to establish the best efficacy and their toxic effects, followed by preclinical trials on a large number of participants. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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20 pages, 4532 KiB  

Open AccessArticle

An Antibacterial Peptide with High Resistance to Trypsin Obtained by Substituting d-Amino Acids for Trypsin Cleavage Sites

by Xiaoou Zhao, Mengna Zhang, Inam Muhammad, Qi Cui, Haipeng Zhang, Yu Jia, Qijun Xu, Lingcong Kong and Hongxia Ma

Antibiotics 2021, 10(12), 1465; https://doi.org/10.3390/antibiotics10121465 - 28 Nov 2021

Cited by 22 | Viewed by 3176

Abstract

The poor stability of antibacterial peptide to protease limits its clinical application. Among these limitations, trypsin mainly exists in digestive tract, which is an insurmountable obstacle to orally delivered peptides. OM19R is a random curly polyproline cationic antimicrobial peptide, which has high antibacterial [...] Read more.

The poor stability of antibacterial peptide to protease limits its clinical application. Among these limitations, trypsin mainly exists in digestive tract, which is an insurmountable obstacle to orally delivered peptides. OM19R is a random curly polyproline cationic antimicrobial peptide, which has high antibacterial activity against some gram-negative bacteria, but its stability against pancreatin is poor. According to the structure-activity relationship of OM19R, all cationic amino acid residues (l-arginine and l-lysine) at the trypsin cleavage sites were replaced with corresponding d-amino acid residues to obtain the designed peptide OM19D, which not only maintained its antibacterial activity but also enhanced the stability of trypsin. Proceeding high concentrations of trypsin and long-time (such as 10 mg/mL, 8 h) treatment, it still had high antibacterial activity (MIC = 16–32 µg/mL). In addition, OM19D also showed high stability to serum, plasma and other environmental factors. It is similar to its parent peptide in secondary structure and mechanism of action. Therefore, this strategy is beneficial to improve the protease stability of antibacterial peptides. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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13 pages, 2928 KiB  

Open AccessArticle

Expression, Purification and Characterization of a Novel Hybrid Peptide CLP with Excellent Antibacterial Activity

by Junhao Cheng, Marhaba Ahmat, Henan Guo, Xubiao Wei, Lulu Zhang, Qiang Cheng, Jing Zhang, Junyong Wang, Dayong Si, Yueping Zhang and Rijun Zhang

Molecules 2021, 26(23), 7142; https://doi.org/10.3390/molecules26237142 - 25 Nov 2021

Cited by 10 | Viewed by 3521

Abstract

CLP is a novel hybrid peptide derived from CM4, LL37 and TP5, with significantly reduced hemolytic activity and increased antibacterial activity than parental antimicrobial peptides. To avoid host toxicity and obtain high-level bio-production of CLP, we established a His-tagged SUMO fusion expression system [...] Read more.

CLP is a novel hybrid peptide derived from CM4, LL37 and TP5, with significantly reduced hemolytic activity and increased antibacterial activity than parental antimicrobial peptides. To avoid host toxicity and obtain high-level bio-production of CLP, we established a His-tagged SUMO fusion expression system in Escherichia coli. The fusion protein can be purified using a Nickel column, cleaved by TEV protease, and further purified in flow-through of the Nickel column. As a result, the recombinant CLP with a yield of 27.56 mg/L and a purity of 93.6% was obtained. The purified CLP exhibits potent antimicrobial activity against gram+ and gram- bacteria. Furthermore, the result of propidium iodide staining and scanning electron microscopy (SEM) showed that CLP can induce the membrane permeabilization and cell death of Enterotoxigenic Escherichia coli (ETEC) K88. The analysis of thermal stability results showed that the antibacterial activity of CLP decreases slightly below 70 °C for 30 min. However, when the temperature was above 70 °C, the antibacterial activity was significantly decreased. In addition, the antibacterial activity of CLP was stable in the pH range from 4.0 to 9.0; however, when pH was below 4.0 and over 9.0, the activity of CLP decreased significantly. In the presence of various proteases, such as pepsin, papain, trypsin and proteinase K, the antibacterial activity of CLP remained above 46.2%. In summary, this study not only provides an effective strategy for high-level production of antimicrobial peptides and evaluates the interference factors that affect the biological activity of hybrid peptide CLP, but also paves the way for further exploration of the treatment of multidrug-resistant bacterial infections. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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16 pages, 2287 KiB  

Open AccessArticle

New Auranofin Analogs with Antibacterial Properties against Burkholderia Clinical Isolates

by Dustin Maydaniuk, Bin Wu, Dang Truong, Sajani H. Liyanage, Andrew M. Hogan, Zhong Ling Yap, Mingdi Yan and Silvia T. Cardona

Antibiotics 2021, 10(12), 1443; https://doi.org/10.3390/antibiotics10121443 - 24 Nov 2021

Cited by 7 | Viewed by 2703

Abstract

Bacteria of the genus Burkholderia include pathogenic Burkholderia mallei, Burkholderia pseudomallei and the Burkholderia cepacia complex (Bcc). These Gram-negative pathogens have intrinsic drug resistance, which makes treatment of infections difficult. Bcc affects individuals with cystic fibrosis (CF) and the species B. cenocepacia [...] Read more.

Bacteria of the genus Burkholderia include pathogenic Burkholderia mallei, Burkholderia pseudomallei and the Burkholderia cepacia complex (Bcc). These Gram-negative pathogens have intrinsic drug resistance, which makes treatment of infections difficult. Bcc affects individuals with cystic fibrosis (CF) and the species B. cenocepacia is associated with one of the worst clinical outcomes. Following the repurposing of auranofin as an antibacterial against Gram-positive bacteria, we previously synthetized auranofin analogs with activity against Gram-negatives. In this work, we show that two auranofin analogs, MS-40S and MS-40, have antibiotic activity against Burkholderia clinical isolates. The compounds are bactericidal against B. cenocepacia and kill stationary-phase cells and persisters without selecting for multistep resistance. Caenorhabditis elegans and Galleria mellonella tolerated high concentrations of MS-40S and MS-40, demonstrating that these compounds have low toxicity in these model organisms. In summary, we show that MS-40 and MS-40S have antimicrobial properties that warrant further investigations to determine their therapeutic potential against Burkholderia infections. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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17 pages, 807 KiB  

Open AccessArticle

Effects of Bacillus amyloliquefaciens LFB112 on Growth Performance, Carcass Traits, Immune, and Serum Biochemical Response in Broiler Chickens

by Marhaba Ahmat, Junhao Cheng, Zaheer Abbas, Qiang Cheng, Zhen Fan, Baseer Ahmad, Min Hou, Ghenijan Osman, Henan Guo, Junyong Wang and Rijun Zhang

Antibiotics 2021, 10(11), 1427; https://doi.org/10.3390/antibiotics10111427 - 22 Nov 2021

Cited by 29 | Viewed by 3223

Abstract

This study aimed to investigate the effects of Bacillus amyloliquefaciens LFB112 on the growth performance, carcass traits, immune response, and serum biochemical parameters of broiler chickens. A total of 396 1 day old, mixed-sex commercial Ross 308 broilers with similar body weights were [...] Read more.

This study aimed to investigate the effects of Bacillus amyloliquefaciens LFB112 on the growth performance, carcass traits, immune response, and serum biochemical parameters of broiler chickens. A total of 396 1 day old, mixed-sex commercial Ross 308 broilers with similar body weights were allotted into six treatment groups. The assigned groups were the CON group (basal diet with no supplement), AB (antibiotics) group (basal diet + 150 mg of aureomycin/kg), C+M group (basal diet + 5 × 10⁸ CFU/kg B. amyloliquefaciens LFB112 powder with vegetative cells + metabolites), C group (basal diet + 5 × 10⁸ CFU/kg B. amyloliquefaciens LFB112 vegetative cell powder with removed metabolites), M group (basal diet + 5 × 10⁸ CFU/kg B. amyloliquefaciens LFB112 metabolite powder with removed vegetative cells), and CICC group (basal diet + 5 × 10⁸ CFU/kg Bacillus subtilis CICC 20179). Results indicated that chickens in the C+M, C, and M groups had higher body weight (BW) and average daily gain (ADG) (p < 0.05) and lower feed conversion ratio (FCR) (p = 0.02) compared to the CON group. The C+M group showed the lowest abdominal fat rate compared to those in the CON, AB, and CICC groups (p < 0.05). Compared to the CON group, serum IgA and IgG levels in the C+M, C, and M groups significantly increased while declining in the AB group (p < 0.05). B. amyloliquefaciens LFB112 supplementation significantly reduced the serum triglyceride, cholesterol, urea, and creatinine levels, while increasing the serum glucose and total protein (p < 0.05). In conclusion, B. amyloliquefaciens LFB112 significantly improved the growth performance, carcass traits, immunity, and blood chemical indices of broiler chickens and may be used as an efficient broiler feed supplement. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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19 pages, 4237 KiB  

Open AccessArticle

Improvement of the Antimicrobial Activity of Oregano Oil by Encapsulation in Chitosan—Alginate Nanoparticles

by Krassimira Yoncheva, Niko Benbassat, Maya M. Zaharieva, Lyudmila Dimitrova, Alexander Kroumov, Ivanka Spassova, Daniela Kovacheva and Hristo M. Najdenski

Molecules 2021, 26(22), 7017; https://doi.org/10.3390/molecules26227017 - 20 Nov 2021

Cited by 39 | Viewed by 9220

Abstract

Oregano oil (OrO) possesses well-pronounced antimicrobial properties but its application is limited due to low water solubility and possible instability. The aim of this study was to evaluate the possibility to incorporate OrO in an aqueous dispersion of chitosan—alginate nanoparticles and how this [...] Read more.

Oregano oil (OrO) possesses well-pronounced antimicrobial properties but its application is limited due to low water solubility and possible instability. The aim of this study was to evaluate the possibility to incorporate OrO in an aqueous dispersion of chitosan—alginate nanoparticles and how this will affect its antimicrobial activity. The encapsulation of OrO was performed by emulsification and consequent electrostatic gelation of both polysaccharides. OrO-loaded nanoparticles (OrO-NP) have small size (320 nm) and negative charge (−25 mV). The data from FTIR spectroscopy and XRD analyses reveal successful encapsulation of the oil into the nanoparticles. The results of thermogravimetry suggest improved thermal stability of the encapsulated oil. The minimal inhibitory concentrations of OrO-NP determined on a panel of Gram-positive and Gram-negative pathogens (ISO 20776-1:2006) are 4–32-fold lower than those of OrO. OrO-NP inhibit the respiratory activity of the bacteria (MTT assay) to a lower extent than OrO; however, the minimal bactericidal concentrations still remain significantly lower. OrO-NP exhibit significantly lower in vitro cytotoxicity than pure OrO on the HaCaT cell line as determined by ISO 10993-5:2009. The irritation test (ISO 10993-10) shows no signs of irritation or edema on the application site. In conclusion, the nanodelivery system of oregano oil possesses strong antimicrobial activity and is promising for development of food additives. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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21 pages, 5208 KiB  

Open AccessArticle

In Silico and In Vitro Evaluation of the Antimicrobial Potential of Bacillus cereus Isolated from Apis dorsata Gut against Neisseria gonorrhoeae

by Nurdjannah Jane Niode, Aryani Adji, Jimmy Rimbing, Max Tulung, Mohammed Alorabi, Ahmed M. El-Shehawi, Rinaldi Idroes, Ismail Celik, Fatimawali, Ahmad Akroman Adam, Kuldeep Dhama, Gomaa Mostafa-Hedeab, Amany Abdel-Rahman Mohamed, Trina Ekawati Tallei and Talha Bin Emran

Antibiotics 2021, 10(11), 1401; https://doi.org/10.3390/antibiotics10111401 - 15 Nov 2021

Cited by 16 | Viewed by 4606

Abstract

Antimicrobial resistance is a major public health and development concern on a global scale. The increasing resistance of the pathogenic bacteria Neisseria gonorrhoeae to antibiotics necessitates efforts to identify potential alternative antibiotics from nature, including insects, which are already recognized as a source [...] Read more.

Antimicrobial resistance is a major public health and development concern on a global scale. The increasing resistance of the pathogenic bacteria Neisseria gonorrhoeae to antibiotics necessitates efforts to identify potential alternative antibiotics from nature, including insects, which are already recognized as a source of natural antibiotics by the scientific community. This study aimed to determine the potential of components of gut-associated bacteria isolated from Apis dorsata, an Asian giant honeybee, as an antibacterial against N. gonorrhoeae by in vitro and in silico methods as an initial process in the stage of new drug discovery. The identified gut-associated bacteria of A. dorsata included Acinetobacter indicus and Bacillus cereus with 100% identity to referenced bacteria from GenBank. Cell-free culture supernatants (CFCS) of B. cereus had a very strong antibacterial activity against N. gonorrhoeae in an in vitro antibacterial testing. Meanwhile, molecular docking revealed that antimicrobial lipopeptides from B. cereus (surfactin, fengycin, and iturin A) had a comparable value of binding-free energy (BFE) with the target protein receptor for N. gonorrhoeae, namely penicillin-binding protein (PBP) 1 and PBP2 when compared with the ceftriaxone, cefixime, and doxycycline. The molecular dynamics simulation (MDS) study revealed that the surfactin remains stable at the active site of PBP2 despite the alteration of the H-bond and hydrophobic interactions. According to this finding, surfactin has the greatest antibacterial potential against PBP2 of N. gonorrhoeae. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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18 pages, 2438 KiB  

Open AccessArticle

Bis(Tryptophan) Amphiphiles Form Ion Conducting Pores and Enhance Antimicrobial Activity against Resistant Bacteria

by Mohit Patel, Saeedeh Negin, Joseph Meisel, Shanheng Yin, Michael Gokel, Hannah Gill and George Gokel

Antibiotics 2021, 10(11), 1391; https://doi.org/10.3390/antibiotics10111391 - 12 Nov 2021

Cited by 1 | Viewed by 2081

Abstract

The compounds referred to as bis(tryptophan)s (BTs) have shown activity as antimicrobials. The hypothesis that the activity of these novel amphiphiles results from insertion in bilayer membranes and transport of cations is supported by planar bilayer voltage-clamp studies reported herein. In addition, [...] Read more.

The compounds referred to as bis(tryptophan)s (BTs) have shown activity as antimicrobials. The hypothesis that the activity of these novel amphiphiles results from insertion in bilayer membranes and transport of cations is supported by planar bilayer voltage-clamp studies reported herein. In addition, fluorescence studies of propidium iodide penetration of vital bacteria confirmed enhanced permeability. It was also found that BTs having either meta-phenylene or n-dodecylene linkers function as effective adjuvants to enhance the properties of FDA-approved antimicrobials against organisms such as S. aureus. In one example, a BT-mediated synergistic effect enhanced the potency of norfloxacin against S. aureus by 128-fold. In order to determine if related compounds in which tryptophan was replaced by other common amino acids (H₂N-Aaa-linker-Aaa-NH₂) we active, a family of analogs have been prepared, characterized, and tested as controls for both antimicrobial activity and as adjuvants for other antimicrobials against both Gram-negative and Gram-positive bacteria. The most active of the compounds surveyed remain the bis(tryptophan) derivatives. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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13 pages, 276 KiB  

Open AccessReview

Artificial Intelligence and Antibiotic Discovery

by Liliana David, Anca Monica Brata, Cristina Mogosan, Cristina Pop, Zoltan Czako, Lucian Muresan, Abdulrahman Ismaiel, Dinu Iuliu Dumitrascu, Daniel Corneliu Leucuta, Mihaela Fadygas Stanculete, Irina Iaru and Stefan Lucian Popa

Antibiotics 2021, 10(11), 1376; https://doi.org/10.3390/antibiotics10111376 - 10 Nov 2021

Cited by 28 | Viewed by 6198

Abstract

Over recent decades, a new antibiotic crisis has been unfolding due to a decreased research in this domain, a low return of investment for the companies that developed the drug, a lengthy and difficult research process, a low success rate for candidate molecules, [...] Read more.

Over recent decades, a new antibiotic crisis has been unfolding due to a decreased research in this domain, a low return of investment for the companies that developed the drug, a lengthy and difficult research process, a low success rate for candidate molecules, an increased use of antibiotics in farms and an overall inappropriate use of antibiotics. This has led to a series of pathogens developing antibiotic resistance, which poses severe threats to public health systems while also driving up the costs of hospitalization and treatment. Moreover, without proper action and collaboration between academic and health institutions, a catastrophic trend might develop, with the possibility of returning to a pre-antibiotic era. Nevertheless, new emerging AI-based technologies have started to enter the field of antibiotic and drug development, offering a new perspective to an ever-growing problem. Cheaper and faster research can be achieved through algorithms that identify hit compounds, thereby further accelerating the development of new antibiotics, which represents a vital step in solving the current antibiotic crisis. The aim of this review is to provide an extended overview of the current artificial intelligence-based technologies that are used for antibiotic discovery, together with their technological and economic impact on the industrial sector. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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7 pages, 7209 KiB  

Open AccessCommunication

Facile Synthesis of 3-Substituted Thiazolo[2,3-?]tetrahydroisoquinolines

by Sheng-Han Huang, Wan-Yu Huang, Guo-Lun Zhang and Te-Fang Yang

Molecules 2021, 26(20), 6126; https://doi.org/10.3390/molecules26206126 - 11 Oct 2021

Cited by 1 | Viewed by 1896

Abstract

It was found that 4-hydroxy-2-butenoic ester (11) could not react with 3,4-dihydro-isoquinoline (4a). Individual addition reactions of ?-mercapto-?,?-unsaturated esters (18) and -unsaturated amide (19) with 3,4-dihydroisoquinolines (4) were carried out under appropriate conditions to provide the corresponding [...] Read more.

It was found that 4-hydroxy-2-butenoic ester (11) could not react with 3,4-dihydro-isoquinoline (4a). Individual addition reactions of ?-mercapto-?,?-unsaturated esters (18) and -unsaturated amide (19) with 3,4-dihydroisoquinolines (4) were carried out under appropriate conditions to provide the corresponding thiazolo[2,3-?]isoquinoline derivatives with good yields (up to 87%) and significant diastereomeric selectivity. The mechanism of the crucial reaction was discussed. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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13 pages, 1364 KiB  

Open AccessArticle

Kinase Inhibitor Library Screening Identifies the Cancer Therapeutic Sorafenib and Structurally Similar Compounds as Strong Inhibitors of the Fungal Pathogen Histoplasma capsulatum

by Charlotte Berkes, Jimmy Franco, Maxx Lawson, Katelynn Brann, Jessica Mermelstein, Daniel Laverty and Allison Connors

Antibiotics 2021, 10(10), 1223; https://doi.org/10.3390/antibiotics10101223 - 8 Oct 2021

Cited by 3 | Viewed by 3146

Abstract

Histoplasma capsulatum is a dimorphic fungal pathogen endemic to the midwestern and southern United States. It causes mycoses ranging from subclinical respiratory infections to severe systemic disease, and is of particular concern for immunocompromised patients in endemic areas. Clinical management of histoplasmosis relies [...] Read more.

Histoplasma capsulatum is a dimorphic fungal pathogen endemic to the midwestern and southern United States. It causes mycoses ranging from subclinical respiratory infections to severe systemic disease, and is of particular concern for immunocompromised patients in endemic areas. Clinical management of histoplasmosis relies on protracted regimens of antifungal drugs whose effectiveness can be limited by toxicity. In this study, we hypothesize that conserved biochemical signaling pathways in the eukaryotic domain can be leveraged to repurpose kinase inhibitors as antifungal compounds. We conducted a screen of two kinase inhibitor libraries to identify compounds inhibiting the growth of Histoplasma capsulatum in the pathogenic yeast form. Our approach identified seven compounds with an elongated hydrophobic polyaromatic structure, five of which share a molecular motif including a urea unit linking a halogenated benzene ring and a para-substituted polyaromatic group. The top hits include the cancer therapeutic Sorafenib, which inhibits growth of Histoplasma in vitro and in a macrophage infection model with low host cell cytotoxicity. Our results reveal the possibility of repurposing Sorafenib or derivatives thereof as therapy for histoplasmosis, and suggest that repurposing of libraries developed for human cellular targets may be a fruitful source of antifungal discovery. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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14 pages, 2319 KiB  

Open AccessArticle

Antiviral Effect of Nonfunctionalized Gold Nanoparticles against Herpes Simplex Virus Type-1 (HSV-1) and Possible Contribution of Near-Field Interaction Mechanism

by Edyta Paradowska, Mirosława Studzińska, Agnieszka Jabłońska, Valeri Lozovski, Natalia Rusinchuk, Iuliia Mukha, Nadiia Vitiuk and Zbigniew J. Leśnikowski

Molecules 2021, 26(19), 5960; https://doi.org/10.3390/molecules26195960 - 1 Oct 2021

Cited by 31 | Viewed by 4152

Abstract

The antiviral activity of nonfunctionalized gold nanoparticles (AuNPs) against herpes simplex virus type-1 (HSV-1) in vitro was revealed in this study. We found that AuNPs are capable of reducing the cytopathic effect (CPE) of HSV-1 in Vero cells in a dose- and time-dependent [...] Read more.

The antiviral activity of nonfunctionalized gold nanoparticles (AuNPs) against herpes simplex virus type-1 (HSV-1) in vitro was revealed in this study. We found that AuNPs are capable of reducing the cytopathic effect (CPE) of HSV-1 in Vero cells in a dose- and time-dependent manner when used in pretreatment mode. The demonstrated antiviral activity was within the nontoxic concentration range of AuNPs. Interestingly, we noted that nanoparticles with smaller sizes reduced the CPE of HSV-1 more effectively than larger ones. The observed phenomenon can be tentatively explained by the near-field action of nanoparticles at the virus envelope. These results show that AuNPs can be considered as potential candidates for the treatment of HSV-1 infections. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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14 pages, 2492 KiB  

Open AccessArticle

Attempts to Access a Series of Pyrazoles Lead to New Hydrazones with Antifungal Potential against Candida species including Azole-Resistant Strains

by Georgiana Negru, Laure Kamus, Elena Bîcu, Sergiu Shova, Boualem Sendid, Faustine Dubar and Alina Ghinet

Molecules 2021, 26(19), 5861; https://doi.org/10.3390/molecules26195861 - 27 Sep 2021

Viewed by 2217

Abstract

The treatment of benzylidenemalononitriles with phenylhydrazines in refluxing ethanol did not provide pyrazole derivatives, but instead furnished hydrazones. The structure of hydrazones was secured by X-ray analysis. The chemical proof was also obtained by direct reaction of 3,4,5-trimethoxybenzaldehyde with 2,4-dichlorophenylhydrazine. Newly synthesized hydrazones [...] Read more.

The treatment of benzylidenemalononitriles with phenylhydrazines in refluxing ethanol did not provide pyrazole derivatives, but instead furnished hydrazones. The structure of hydrazones was secured by X-ray analysis. The chemical proof was also obtained by direct reaction of 3,4,5-trimethoxybenzaldehyde with 2,4-dichlorophenylhydrazine. Newly synthesized hydrazones were tested against eight Candida spp. strains in a dose response assay to determine the minimum inhibitory concentration (MIC₉₉). Five compounds were identified as promising antifungal agents against Candida spp. (C. albicans SC5314, C. glabrata, C. tropicalis, C. parapsilosis and C. glabrata (R azoles)), with MIC₉₉ values ranging from 16 to 32 µg/mL and selective antifungal activity over cytotoxicity. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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15 pages, 5841 KiB  

Open AccessArticle

Therapeutic Efficacy of Sesquiterpene Farnesol in Treatment of Cutibacterium acnes-Induced Dermal Disorders

by Guan-Xuan Wu, Yu-Wen Wang, Chun-Shien Wu, Yen-Hung Lin, Chih-Hsin Hung, Han-Hsiang Huang and Shyh-Ming Kuo

Molecules 2021, 26(18), 5723; https://doi.org/10.3390/molecules26185723 - 21 Sep 2021

Cited by 8 | Viewed by 3565

Abstract

Acne vulgaris is a highly prevalent skin disorder requiring treatment and management by dermatologists. Antibiotics such as clindamycin are commonly used to treat acne vulgaris. However, from both medical and public health perspectives, the development of alternative remedies has become essential due to [...] Read more.

Acne vulgaris is a highly prevalent skin disorder requiring treatment and management by dermatologists. Antibiotics such as clindamycin are commonly used to treat acne vulgaris. However, from both medical and public health perspectives, the development of alternative remedies has become essential due to the increase in antibiotic resistance. Topical therapy is useful as a single or combined treatment for mild and moderate acne and is often employed as maintenance therapy. Thus, the current study investigated the anti-inflammatory, antibacterial, and restorative effects of sesquiterpene farnesol on acne vulgaris induced by Cutibacterium acnes (C. acnes) in vitro and in a rat model. The minimum inhibitory concentration (MIC) of farnesol against C. acnes was 0.14 mM, and the IC₅₀ of 24 h exposure to farnesol in HaCaT keratinocytes was approximately 1.4 mM. Moreover, 0.8 mM farnesol exhibited the strongest effects in terms of the alleviation of inflammatory responses and abscesses and necrotic tissue repair in C.acnes-induced acne lesions; 0.4 mM farnesol and clindamycin gel also exerted similar actions after a two-time treatment. By contrast, nearly doubling the tissue repair scores, 0.4 mM farnesol displayed great anti-inflammatory and the strongest reparative actions after a four-time treatment, followed by 0.8 mM farnesol and a commercial gel. Approximately 2–10-fold decreases in interleukin (IL)-1?, IL-6, and tumor necrosis factor (TNF)-?, found by Western blot analysis, were predominantly consistent with the histopathological findings and tissue repair scores. The basal hydroxypropyl methylcellulose (HPMC) gel did not exert anti-inflammatory or reparative effects on rat acne lesions. Our results suggest that the topical application of a gel containing farnesol is a promising alternative remedy for acne vulgaris. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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20 pages, 4077 KiB  

Open AccessReview

Nano-Drug Design Based on the Physiological Properties of Glutathione

by Wenhua Li, Minghui Li and Jing Qi

Molecules 2021, 26(18), 5567; https://doi.org/10.3390/molecules26185567 - 13 Sep 2021

Cited by 18 | Viewed by 4845

Abstract

Glutathione (GSH) is involved in and regulates important physiological functions of the body as an essential antioxidant. GSH plays an important role in anti-oxidation, detoxification, anti-aging, enhancing immunity and anti-tumor activity. Herein, based on the physiological properties of GSH in different diseases, mainly [...] Read more.

Glutathione (GSH) is involved in and regulates important physiological functions of the body as an essential antioxidant. GSH plays an important role in anti-oxidation, detoxification, anti-aging, enhancing immunity and anti-tumor activity. Herein, based on the physiological properties of GSH in different diseases, mainly including the strong reducibility of GSH, high GSH content in tumor cells, and the NADPH depletion when GSSH is reduced to GSH, we extensively report the design principles, effect, and potential problems of various nano-drugs in diabetes, cancer, nervous system diseases, fluorescent probes, imaging, and food. These studies make full use of the physiological and pathological value of GSH and develop excellent design methods of nano-drugs related to GSH, which shows important scientific significance and prominent application value for the related diseases research that GSH participates in or responds to. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies)

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