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Antibiotics
Special Issues
Design and Synthesis of Novel Antibiotics
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Design and Synthesis of Novel Antibiotics

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Novel Antimicrobial Agents".

Deadline for manuscript submissions: closed (31 August 2024) | Viewed by 23135

Special Issue Editors

Dr. Katarzyna Turecka

E-Mail Website
Guest Editor
Katedra i Zakład Mikrobiologii Farmaceutycznej, Gdański Uniwersytet Medyczny, Gdańsk, Poland
Interests: pharmaceutical microbiology; antibacterial compounds; antifungals; medical chemistry; molecular biology
Dr. Kenneth Ikenna Onyedibe

E-Mail Website
Guest Editor
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA
Interests: antibiotic resistance; emerging pathogens; immune signaling; drug discovery

Special Issue Information

Dear Colleagues,

The increasing resistance of microorganisms to the currently available antimicrobials is a serious problem globally, resulting in significant morbidity, mortality and healthcare costs. Antimicrobial resistance occurs naturally over time and appears in microorganisms due to the selective pressure caused by the use of antimicrobial compounds. Sensitive microorganisms become resistant as a result of changes in their genome. The problem of antimicrobial resistance is especially urgent in terms of antibiotic resistance bacteria, and especially alarming is the rapid global spread of multi- and pan-resistant bacteria. Bacteria are undergoing evolutionary changes, and their adaptive abilities lead to the development of drug resistance. The occurrence of antimicrobial drug resistance among microorganisms is associated with the constantly increasing consumption of these kinds of compounds in therapy and increasing concentrations in the environment as an effect of human activity in agriculture or the food industry. Thus, there is an urgent need to search for new, alternative classes of effective antibiotics with novel modes of action and low toxicity.

This Special Issue, "Design and Synthesis of Novel Antibiotics", aims to present the latest scientific research in the field of the design, synthesis, characterization and development of new antibiotics. The manuscript should include the structural characterization of new compounds and the evaluation of their biological activity and cytotoxicity. Reviews and research articles will be considered for publication.

Dr. Katarzyna Turecka
Dr. Kenneth Ikenna Onyedibe
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug discovery
  • antimicrobial modes of action
  • antimicrobial resistance
  • structural characterization
  • antimicrobial activity

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Published Papers (8 papers)

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Research

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21 pages, 3351 KiB  
Article
A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens
by Eric J. Bryan, Qi Qiao, Yuxuan Wang, Jacques Y. Roberge, Edmond J. LaVoie and Daniel S. Pilch
Antibiotics 2024, 13(3), 209; https://doi.org/10.3390/antibiotics13030209 - 22 Feb 2024
Cited by 1 | Viewed by 2163
Abstract
The global threat of multidrug-resistant Gram-negative bacterial pathogens necessitates the development of new and effective antibiotics. FtsZ is an essential and highly conserved cytoskeletal protein that is an appealing antibacterial target for new antimicrobial therapeutics. However, the effectiveness of FtsZ inhibitors against Gram-negative [...] Read more.
The global threat of multidrug-resistant Gram-negative bacterial pathogens necessitates the development of new and effective antibiotics. FtsZ is an essential and highly conserved cytoskeletal protein that is an appealing antibacterial target for new antimicrobial therapeutics. However, the effectiveness of FtsZ inhibitors against Gram-negative species has been limited due in part to poor intracellular accumulation. To address this limitation, we have designed a FtsZ inhibitor (RUP4) that incorporates a chlorocatechol siderophore functionality that can chelate ferric iron (Fe3+) and utilizes endogenous siderophore uptake pathways to facilitate entry into Gram-negative pathogens. We show that RUP4 is active against both Klebsiella pneumoniae and Acinetobacter baumannii, with this activity being dependent on direct Fe3+ chelation and enhanced under Fe3+-limiting conditions. Genetic deletion studies in K. pneumoniae reveal that RUP4 gains entry through the FepA and CirA outer membrane transporters and the FhuBC inner membrane transporter. We also show that RUP4 exhibits bactericidal synergy against K. pneumoniae when combined with select antibiotics, with the strongest synergy observed with PBP2-targeting β-lactams or MreB inhibitors. In the aggregate, our studies indicate that incorporation of Fe3+-chelating moieties into FtsZ inhibitors is an appealing design strategy for enhancing activity against Gram-negative pathogens of global clinical significance. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Antibiotics)
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21 pages, 3033 KiB  
Article
Activity of Cinnamic Acid Derivatives with 4-Chloro-2-mercaptobenzenesulfonamide Moiety against Clinical HLAR and VRE Enterococcus spp.
by Rafał Hałasa, Anita Bułakowska, Jarosław Sławiński, Magdalena Smoktunowicz, Aleksandra Rapacka-Zdończyk and Urszula Mizerska
Antibiotics 2023, 12(12), 1691; https://doi.org/10.3390/antibiotics12121691 - 2 Dec 2023
Cited by 1 | Viewed by 1593
Abstract
The rapid increase in strains that are resistant to antibiotics requires new active compounds to be found whose mechanism of action on bacteria is different to those that are currently known. Of particular interest are compounds that occur in plants as secondary metabolites. [...] Read more.
The rapid increase in strains that are resistant to antibiotics requires new active compounds to be found whose mechanism of action on bacteria is different to those that are currently known. Of particular interest are compounds that occur in plants as secondary metabolites. The focus of this study concerns the examination of the effects of synthetic cinnamic acid derivatives, with 4-chloro-2-mercaptobenzenesulfonamide moiety on Enterococcus spp. with HLAR (high-level aminoglycoside resistance) and VRE (vancomycin-resistant Enterococcus) mechanisms. The minimum inhibitory concentration (MIC) values of the tested compounds were determined using the serial dilution method for Enterococcus spp. groups, and the most active compounds were as follows: 16d, 17c, 16a, 16c and 16f (2–4 µg/mL). These compounds, at a concentration of 4 × MIC, inhibited the biofilm formation of HLAR strains (70 to 94%). At concentrations of 2 × MIC and 4 × MIC, they also inhibited the growth of VRE strains (42 to 96%). The best effect produced on the formed biofilm was demonstrated by compound 16f (from 62% MIC concentration to 89% 4 × MIC concentration) on the tested HLAR strains. In vitro studies, using the peripheral blood of domestic sheep, demonstrated the stable bacteriostatic activity of the tested compounds against Enterococcus spp. The compounds 16a, 16c, 16d, 16f and 17c showed synergism and additivity with ampicillin, streptomycin, gentamicin and vancomycin against resistant strains of Enterococcus spp. The tested compounds, when combined, reduce the MIC for antibiotics by 800 to 10,000 times for HLAR strains and by 8 to 10,000 times for VRE strains. The MIC of the tested compounds, in combination with antibiotics, is reduced 2–16-fold for HLAR strains and 2–32-fold for VRE strains. These studies demonstrate the potential for the therapeutic use of synthetic, cinnamic acid derivatives, with 4-chloro-2-mercaptobenzenesulfonamide moiety, to work against clinical strains of Enterococcus spp. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Antibiotics)
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23 pages, 8070 KiB  
Article
Saponin-Derived Silver Nanoparticles from Phoenix dactylifera (Ajwa Dates) Exhibit Broad-Spectrum Bioactivities Combating Bacterial Infections
by Mohd Adnan, Arif Jamal Siddiqui, Syed Amir Ashraf, Mohammad Saquib Ashraf, Sarah Owdah Alomrani, Mousa Alreshidi, Bektas Tepe, Manojkumar Sachidanandan, Corina Danciu and Mitesh Patel
Antibiotics 2023, 12(9), 1415; https://doi.org/10.3390/antibiotics12091415 - 7 Sep 2023
Cited by 6 | Viewed by 2231
Abstract
The emergence of antibiotic resistance poses a serious threat to humankind, emphasizing the need for alternative antimicrobial agents. This study focuses on investigating the antibacterial, antibiofilm, and anti-quorum-sensing (anti-QS) activities of saponin-derived silver nanoparticles (AgNPs-S) obtained from Ajwa dates (Phoenix dactylifera L.). [...] Read more.
The emergence of antibiotic resistance poses a serious threat to humankind, emphasizing the need for alternative antimicrobial agents. This study focuses on investigating the antibacterial, antibiofilm, and anti-quorum-sensing (anti-QS) activities of saponin-derived silver nanoparticles (AgNPs-S) obtained from Ajwa dates (Phoenix dactylifera L.). The design and synthesis of these novel nanoparticles were explored in the context of developing alternative strategies to combat bacterial infections. The Ajwa date saponin extract was used as a reducing and stabilizing agent to synthesize AgNPs-S, which was characterized using various analytical techniques, including UV–Vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). The biosynthesized AgNPs-S exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria due to their capability to disrupt bacterial cell membranes and the leakage of nucleic acid and protein contents. The AgNPs-S effectively inhibited biofilm formation and quorum-sensing (QS) activity by interfering with QS signaling molecules, which play a pivotal role in bacterial virulence and pathogenicity. Furthermore, the AgNPs-S demonstrated significant antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals and cytotoxicity against small lung cancer cells (A549 cells). Overall, the findings of the present study provide valuable insights into the potential use of these nanoparticles as alternative therapeutic agents for the design and development of novel antibiotics. Further investigations are warranted to elucidate the possible mechanism involved and safety concerns when it is used in vivo, paving the way for future therapeutic applications in combating bacterial infections and overcoming antibiotic resistance. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Antibiotics)
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11 pages, 1765 KiB  
Article
Integration of Antimicrobials and Delivery Systems: Synergistic Antibiofilm Activity with Biodegradable Nanoemulsions Incorporating Pseudopyronine Analogs
by Jungmi Park, Neel Mahida, Gabrielle Ho, Elizabeth Pena, Jessa Marie V. Makabenta, Stanley Aneke, Mingdi Jiang, Leah M. Bouthillette, Stephanie E. Holz, Muhammad Aamir Hassan, Amanda L. Wolfe and Vincent M. Rotello
Antibiotics 2023, 12(8), 1240; https://doi.org/10.3390/antibiotics12081240 - 28 Jul 2023
Cited by 4 | Viewed by 1859
Abstract
Multi-drug-resistant (MDR) bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), pose a significant challenge in healthcare settings. Small molecule antimicrobials (SMAs) such as α-pyrones have shown promise as alternative treatments for MDR infections. However, the hydrophobic nature of many SMAs limits their solubility and efficacy [...] Read more.
Multi-drug-resistant (MDR) bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), pose a significant challenge in healthcare settings. Small molecule antimicrobials (SMAs) such as α-pyrones have shown promise as alternative treatments for MDR infections. However, the hydrophobic nature of many SMAs limits their solubility and efficacy in complex biological environments. In this study, we encapsulated pseudopyronine analogs (PAs) in biodegradable polymer nanoemulsions (BNEs) for efficient eradication of biofilms. We evaluated a series of PAs with varied alkyl chain lengths and examined their antimicrobial activity against Gram-positive pathogens (S. aureus, MRSA, and B. subtilis). The selected PA with the most potent antibiofilm activity was incorporated into BNEs for enhanced solubility and penetration into the EPS matrix (PA-BNEs). The antimicrobial efficacy of PA-BNEs was assessed against biofilms of Gram-positive strains. The BNEs facilitated the solubilization and effective delivery of the PA deep into the biofilm matrix, addressing the limitations of hydrophobic SMAs. Our findings demonstrated that the PA2 exhibited synergistic antibiofilm activity when it was loaded into nanoemulsions. This study presents a promising platform for addressing MDR infections by combining pseudopyronine analogs with antimicrobial biodegradable nanoemulsions, overcoming challenges associated with treating biofilm infections. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Antibiotics)
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15 pages, 9462 KiB  
Article
Discovery of Bactericidal Proteins from Staphylococcus Phage Stab21 Using a High-Throughput Screening Method
by Ellisiv Nyhamar, Paige Webber, Olivia Liong, Özgenur Yilmaz, Maria Pajunen, Mikael Skurnik and Xing Wan
Antibiotics 2023, 12(7), 1213; https://doi.org/10.3390/antibiotics12071213 - 21 Jul 2023
Viewed by 1590
Abstract
In the escalating battle against antimicrobial resistance, there is an urgent need to discover and investigate new antibiotic strategies. Bacteriophages are untapped reservoirs of such potential antimicrobials. This study focused on Hypothetical Proteins of Unknown Function (HPUFs) from a Staphylococcus phage Stab21. We [...] Read more.
In the escalating battle against antimicrobial resistance, there is an urgent need to discover and investigate new antibiotic strategies. Bacteriophages are untapped reservoirs of such potential antimicrobials. This study focused on Hypothetical Proteins of Unknown Function (HPUFs) from a Staphylococcus phage Stab21. We examined its HPUFs for bactericidal activity against E. coli using a Next Generation Sequencing (NGS)-based approach. Among the 96 HPUFs examined, 5 demonstrated cross-species toxicity towards E. coli, suggesting the presence of shared molecular targets between E. coli and S. aureus. One toxic antibacterial HPUF (toxHPUF) was found to share homology with a homing endonuclease. The implications of these findings are profound, particularly given the potential broad applicability of these bactericidal agents. This study confirms the efficacy of NGS in streamlining the screening process of toxHPUFs, contributes significantly to the ongoing exploration of phage biology, and offers promises in the search for potent antimicrobial agents. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Antibiotics)
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21 pages, 3601 KiB  
Article
Biosynthesized Silver Nanoparticles Derived from Probiotic Lactobacillus rhamnosus (AgNPs-LR) Targeting Biofilm Formation and Quorum Sensing-Mediated Virulence Factors
by Amir Mahgoub Awadelkareem, Arif Jamal Siddiqui, Emira Noumi, Syed Amir Ashraf, Sibte Hadi, Mejdi Snoussi, Riadh Badraoui, Fevzi Bardakci, Mohammad Saquib Ashraf, Corina Danciu, Mitesh Patel and Mohd Adnan
Antibiotics 2023, 12(6), 986; https://doi.org/10.3390/antibiotics12060986 - 31 May 2023
Cited by 9 | Viewed by 2487
Abstract
In recent years, bacterial pathogens have developed resistance to antimicrobial agents that have created a global threat to human health and environment. As a novel approach to combating antimicrobial resistance (AMR), targeting bacteria’s virulent traits that can be explained by quorum sensing (QS) [...] Read more.
In recent years, bacterial pathogens have developed resistance to antimicrobial agents that have created a global threat to human health and environment. As a novel approach to combating antimicrobial resistance (AMR), targeting bacteria’s virulent traits that can be explained by quorum sensing (QS) is considered to be one of the most promising approaches. In the present study, biologically synthesized silver nanoparticles derived from Lactobacillus rhamnosus (AgNPs-LR) were tested against three Gram-negative bacteria to determine whether they inhibited the formation of biofilms and triggered the virulence factors controlled by QS. In C. violaceum and S. marcescens, a remarkable inhibition (>70%) of QS-mediated violacein and prodigiosin production was recorded, respectively. A dose-dependent decrease in virulence factors of P. aeruginosa (pyocyanin, pyoverdine, LasA protease, LasB elastase and rhamnolipid production) was also observed with AgNPs-LR. The biofilm development was reduced by 72.56%, 61.70%, and 64.66% at highest sub-MIC for C. violaceum, S. marcescens and P. aeruginosa, respectively. Observations on glass surfaces have shown remarkable reductions in biofilm formation, with less aggregation of bacteria and a reduced amount of extra polymeric materials being formed from the bacteria. Moreover, swimming motility and exopolysaccharides (EPS) was also found to reduce in the presence of AgNPs-LR. Therefore, these results clearly demonstrate that AgNPs-LR is highly effective in inhibiting the development of biofilms and the QS-mediated virulent traits of Gram-negative bacteria. In the future, AgNPs-LR may be used as an alternative to conventional antibiotics for the treatment of bacterial infections after careful evaluation in animal models, especially for the development of topical antimicrobial agents. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Antibiotics)
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Review

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20 pages, 10053 KiB  
Review
A Comprehensive Review on Significance and Advancements of Antimicrobial Agents in Biodegradable Food Packaging
by Ipsheta Bose, Swarup Roy, Vinay Kumar Pandey and Rahul Singh
Antibiotics 2023, 12(6), 968; https://doi.org/10.3390/antibiotics12060968 - 26 May 2023
Cited by 23 | Viewed by 5609
Abstract
Food waste is key global problem and more than 90% of the leftover waste produced by food packaging factories is dumped in landfills. Foods packaged using eco-friendly materials have a longer shelf life as a result of the increased need for high-quality and [...] Read more.
Food waste is key global problem and more than 90% of the leftover waste produced by food packaging factories is dumped in landfills. Foods packaged using eco-friendly materials have a longer shelf life as a result of the increased need for high-quality and secure packaging materials. For packaging purposes, natural foundation materials are required, as well as active substances that can prolong the freshness of the food items. Antimicrobial packaging is one such advancement in the area of active packaging. Biodegradable packaging is a basic form of packaging that will naturally degrade and disintegrate in due course of time. A developing trend in the active and smart food packaging sector is the use of natural antioxidant chemicals and inorganic nanoparticles (NPs). The potential for active food packaging applications has been highlighted by the incorporation of these materials, such as polysaccharides and proteins, in biobased and degradable matrices, because of their stronger antibacterial and antioxidant properties, UV-light obstruction, water vapor permeability, oxygen scavenging, and low environmental impact. The present review highlights the use of antimicrobial agents and nanoparticles in food packaging, which helps to prevent undesirable changes in the food, such as off flavors, colour changes, or the occurrence of any foodborne outcomes. This review attempts to cover the most recent advancements in antimicrobial packaging, whether edible or not, employing both conventional and novel polymers as support, with a focus on natural and biodegradable ingredients. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Antibiotics)
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25 pages, 4852 KiB  
Review
Synthetic and Semisynthetic Compounds as Antibacterials Targeting Virulence Traits in Resistant Strains: A Narrative Updated Review
by Dejan Stojković, Jovana Petrović, Tamara Carević, Marina Soković and Konstantinos Liaras
Antibiotics 2023, 12(6), 963; https://doi.org/10.3390/antibiotics12060963 - 25 May 2023
Cited by 10 | Viewed by 4252
Abstract
This narrative review paper provides an up-to-date overview of the potential of novel synthetic and semisynthetic compounds as antibacterials that target virulence traits in resistant strains. The review focused on research conducted in the last five years and investigated a range of compounds [...] Read more.
This narrative review paper provides an up-to-date overview of the potential of novel synthetic and semisynthetic compounds as antibacterials that target virulence traits in resistant strains. The review focused on research conducted in the last five years and investigated a range of compounds including azoles, indoles, thiophenes, glycopeptides, pleuromutilin derivatives, lactone derivatives, and chalcones. The emergence and spread of antibiotic-resistant bacterial strains is a growing public health concern, and new approaches are urgently needed to combat this threat. One promising approach is to target virulence factors, which are essential for bacterial survival and pathogenesis, but not for bacterial growth. By targeting virulence factors, it may be possible to reduce the severity of bacterial infections without promoting the development of resistance. We discuss the mechanisms of action of the various compounds investigated and their potential as antibacterials. The review highlights the potential of targeting virulence factors as a promising strategy to combat antibiotic resistance and suggests that further research is needed to identify new compounds and optimize their efficacy. The findings of this review suggest that novel synthetic and semisynthetic compounds that target virulence factors have great potential as antibacterials in the fight against antibiotic resistance. Full article
(This article belongs to the Special Issue Design and Synthesis of Novel Antibiotics)
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