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16 pages, 12242 KiB

Open AccessArticle

Veratryl Alcohol Attenuates the Virulence and Pathogenicity of Pseudomonas aeruginosa Mainly via Targeting las Quorum-Sensing System

by Songzhe Fu, Wenxu Song, Xiaofeng Han, Lin Chen and Lixin Shen

Microorganisms 2024, 12(5), 985; https://doi.org/10.3390/microorganisms12050985 - 14 May 2024

Viewed by 1364

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen that usually causes chronic infections and even death in patients. The treatment of P. aeruginosa infection has become more challenging due to the prevalence of antibiotic resistance and the slow pace of new antibiotic development. Therefore, it [...] Read more.

Pseudomonas aeruginosa is an opportunistic pathogen that usually causes chronic infections and even death in patients. The treatment of P. aeruginosa infection has become more challenging due to the prevalence of antibiotic resistance and the slow pace of new antibiotic development. Therefore, it is essential to explore non-antibiotic methods. A new strategy involves screening for drugs that target the quorum-sensing (QS) system. The QS system regulates the infection and drug resistance in P. aeruginosa. In this study, veratryl alcohol (VA) was found as an effective QS inhibitor (QSI). It effectively suppressed the expression of QS-related genes and the subsequent production of virulence factors under the control of QS including elastase, protease, pyocyanin and rhamnolipid at sub-inhibitory concentrations. In addition, motility activity and biofilm formation, which were correlated with the infection of P. aeruginosa, were also suppressed by VA. In vivo experiments demonstrated that VA could weaken the pathogenicity of P. aeruginosa in Chinese cabbage, Drosophila melanogaster, and Caenorhabditis elegans infection models. Molecular docking, combined with QS quintuple mutant infection analysis, identified that the mechanism of VA could target the LasR protein of the las system mainly. Moreover, VA increased the susceptibility of P. aeruginosa to conventional antibiotics of tobramycin, kanamycin and gentamicin. The results firstly demonstrate that VA is a promising QSI to treat infections caused by P. aeruginosa. Full article

(This article belongs to the Special Issue Advances in Novel Antibacterial Agents)

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17 pages, 19177 KiB

Open AccessArticle

Antibacterial Mechanisms and Antivirulence Activities of Oridonin against Pathogenic Aeromonas hydrophila AS 1.1801

by Lunji Wang, Huijuan Li, Jinhao Chen, Yi Wang, Yuqing Gu and Min Jiu

Microorganisms 2024, 12(2), 415; https://doi.org/10.3390/microorganisms12020415 - 19 Feb 2024

Cited by 3 | Viewed by 1758

Abstract

Aeromonas hydrophila, a Gram-negative bacterium widely found in freshwater environments, acts as a common conditional pathogen affecting humans, livestock, and aquatic animals. In this study, the impact of oridonin, an ent-kaurane diterpenoid compound derived from Rabdosia rubescens, on the virulence [...] Read more.

Aeromonas hydrophila, a Gram-negative bacterium widely found in freshwater environments, acts as a common conditional pathogen affecting humans, livestock, and aquatic animals. In this study, the impact of oridonin, an ent-kaurane diterpenoid compound derived from Rabdosia rubescens, on the virulence factors of A. hydrophila AS 1.1801 and its antibacterial mechanism was elucidated. The minimum inhibitory concentration (MIC) of oridonin against A. hydrophila AS 1.1801 was 100 μg/mL. Oridonin at inhibitory concentrations could significantly increase the electrical conductivity in the supernatant and escalate nucleic acid leakage (p < 0.01). This effect was concomitant with observed distortions in bacterial cells, the formation of cytoplasmic cavities, cellular damage, and pronounced inhibition of protein and nucleic acid synthesis. Additionally, oridonin at inhibitory levels exhibited a noteworthy suppressive impact on A. hydrophila AS 1.1801 across biofilm formation, motility, hemolytic activity, lipase activity, and protease activity (p < 0.05), demonstrating a dose-dependent enhancement. qRT-PCR analysis showed that the gene expression of luxR, qseB and omp were significantly downregulated after oridonin treatment in A. hydrophila AS 1.1801 (p < 0.05). Our results indicated that oridonin possessed significant antibacterial and anti-virulence effects on A. hydrophila AS 1.1801. Full article

(This article belongs to the Special Issue Advances in Novel Antibacterial Agents)

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13 pages, 2367 KiB

Open AccessArticle

Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics

by Zhiyu Zhou, Ruddy Wattiez, Patricia Constant, Hedia Marrakchi, Karine Soetaert, Vanessa Mathys, Véronique Fontaine and Sheng Zeng

Microorganisms 2023, 11(10), 2469; https://doi.org/10.3390/microorganisms11102469 - 30 Sep 2023

Cited by 1 | Viewed by 1391

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a public health issue, particularly due to multi-drug-resistant Mtb. The bacillus is wrapped in a waxy envelope containing lipids acting as essential virulence factors, accounting for the natural antibiotic resistance of mycobacteria. Telacebec (previously known [...] Read more.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a public health issue, particularly due to multi-drug-resistant Mtb. The bacillus is wrapped in a waxy envelope containing lipids acting as essential virulence factors, accounting for the natural antibiotic resistance of mycobacteria. Telacebec (previously known as Q203) is a promising new anti-TB agent inhibiting the cytochrome bc₁ complex of a mycobacterial electron transport chain (ETC). Here, we show that the telacebec-challenged M. bovis BCG exhibited a reduced expression of proteins involved in the synthesis of phthiocerol dimycocerosates (PDIMs)/phenolic glycolipids (PGLs), lipid virulence factors associated with cell envelope impermeability. Consistently, telacebec, at concentrations lower than its MIC, downregulated the transcription of a PDIM/PGL-synthesizing operon, suggesting a metabolic vulnerability triggered by the drug. The drug was able to synergize on BCG with rifampicin or vancomycin, the latter being a drug exerting a marginal effect on PDIM-bearing bacilli. Telacebec at a concentration higher than its MIC had no detectable effect on cell wall PDIMs, as shown by TLC analysis, a finding potentially explained by the retaining of previously synthesized PDIMs due to the inhibition of growth. The study extends the potential of telacebec, demonstrating an effect on mycobacterial virulence lipids, allowing for the development of new anti-TB strategies. Full article

(This article belongs to the Special Issue Advances in Novel Antibacterial Agents)

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18 pages, 5083 KiB

Open AccessArticle

Changes in the Ultrastructure of Staphylococcus aureus Cells Make It Possible to Identify and Analyze the Injuring Effects of Ciprofloxacin, Polycationic Amphiphile and Their Hybrid

by Alina E. Grigor’eva, Alevtina V. Bardasheva, Elena S. Ryabova, Anastasiya V. Tupitsyna, Danila A. Zadvornykh, Lyudmila S. Koroleva, Vladimir N. Silnikov, Nina V. Tikunova and Elena I. Ryabchikova

Microorganisms 2023, 11(9), 2192; https://doi.org/10.3390/microorganisms11092192 - 30 Aug 2023

Cited by 2 | Viewed by 1450

Abstract

The purposeful development of synthetic antibacterial compounds requires an understanding of the relationship between effects of compounds and their chemical structure. This knowledge can be obtained by studying changes in bacteria ultrastructure under the action of antibacterial compounds of a certain chemical structure. [...] Read more.

The purposeful development of synthetic antibacterial compounds requires an understanding of the relationship between effects of compounds and their chemical structure. This knowledge can be obtained by studying changes in bacteria ultrastructure under the action of antibacterial compounds of a certain chemical structure. Our study was aimed at examination of ultrastructural changes in S. aureus cells caused by polycationic amphiphile based on 1,4‒diazabicyclo[2.2.2]octane (DL₄12), ciprofloxacin and their hybrid (DL₅Cip6); the samples were incubated for 15 and 45 min. DL₄12 first directly interacted with bacterial cell wall, damaging it, then penetrated into the cell and disrupted cytoplasm. Ciprofloxacin penetrated into cell without visually damaging the cell wall, but altered the cell membrane and cytoplasm, and inhibited the division of bacteria. The ultrastructural characteristics of S. aureus cells damaged by the hybrid clearly differed from those under ciprofloxacin or DL₄12 action. Signs associated with ciprofloxacin predominated in cell damage patterns from the hybrid. We studied the effect of ciprofloxacin, DL₄12 and their hybrid on S. aureus biofilm morphology using paraffin sections. Clear differences in compound effects on S. aureus biofilm (45 min incubation) were observed. The results obtained allow us to recommend this simple and cheap approach for the initial assessment of antibiofilm properties of synthesized compounds. Full article

(This article belongs to the Special Issue Advances in Novel Antibacterial Agents)

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13 pages, 3634 KiB

Open AccessArticle

Native Pig Neutrophil Products: Insights into Their Antimicrobial Activity

by Eric Fernández-De La Cruz, Joanna Wessely-Szponder, Miguel Viñas, Teresa Vinuesa, Alexandra Merlos, Marta Jorba, Paula Espinal and Ester Fusté

Microorganisms 2023, 11(8), 2119; https://doi.org/10.3390/microorganisms11082119 - 20 Aug 2023

Viewed by 1407

Abstract

Cationic antimicrobial peptides are molecules with potential applications for treating infections due to their antimicrobial and immunomodulatory properties. The aim of this work was to explore the antimicrobial activity and mechanisms of action of a porcine neutrophil cathelicidin mixture (MPPN). Gram-positive and Gram-negative [...] Read more.

Cationic antimicrobial peptides are molecules with potential applications for treating infections due to their antimicrobial and immunomodulatory properties. The aim of this work was to explore the antimicrobial activity and mechanisms of action of a porcine neutrophil cathelicidin mixture (MPPN). Gram-positive and Gram-negative bacteria were used to determine the minimum inhibitory concentration (MIC) and experiments of both time–kill kinetics and effects on growth curves were performed. Planar black lipid bilayer conductance was measured to analyze the interaction of MPPN with lipid bilayers. Visualization of bacterial surfaces and membrane alterations was achieved using atomic force microscopy and transmission electron microscopy. The effects on the activity of efflux pumps (EPs) were studied with an intracellular accumulation of acridine orange (AO) assay. In E. coli, MPPN behaves as a bactericide at high concentrations and as a bacteriostatic at lower concentrations. The bacteriostatic effect was also observed for slightly shorter periods in S. enterica. The mixture was not active on S. aureus. The increase in AO accumulation in the presence of MPPN indicates that, at least in E. coli, the mixture causes inhibition of the EP function. Observed and detected variable conductance events demonstrate a strong MPPN effect on lipid bilayers. Damage to the structure of treated E. coli indicates that MPPN induces alterations in the bacterial surface. The use of AMPs capable of inhibiting EP can be seen as a good tool to combat antimicrobial resistance since they could be used alone or in combination with other conventional antibiotics to which bacteria have become resistant. Full article

(This article belongs to the Special Issue Advances in Novel Antibacterial Agents)

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20 pages, 4151 KiB

Open AccessArticle

Direct Detection of Antibacterial-Producing Soil Isolates Utilizing a Novel High-Throughput Screening Assay

by Wikus Ernst Laubscher and Marina Rautenbach

Microorganisms 2022, 10(11), 2235; https://doi.org/10.3390/microorganisms10112235 - 11 Nov 2022

Cited by 3 | Viewed by 4656

Abstract

The ever-increasing global threat of common infections developing resistance to current therapeutics is rapidly accelerating the onset of a primitive post-antibiotic era in medicine. The prevention of further antimicrobial resistance development is unlikely due to the continued misuse of antibiotics, augmented by the [...] Read more.

The ever-increasing global threat of common infections developing resistance to current therapeutics is rapidly accelerating the onset of a primitive post-antibiotic era in medicine. The prevention of further antimicrobial resistance development is unlikely due to the continued misuse of antibiotics, augmented by the lack of discovery of novel antibiotics. Screening large libraries of synthetic compounds have yet to offer effective replacements for current antibiotics. Due to historical successes, discovery from large and diverse natural sources and, more specifically, environmental bacteria, may still yield novel alternative antibiotics. However, the process of antibiotic discovery from natural sources is laborious and time-consuming as a result of outdated methodologies. Therefore, we have developed a simple and rapid preliminary screening assay to identify antibacterial-producing bacteria from natural sources. In brief, the assay utilizes the presence or absence of luminescence in bioluminescent reporter bacteria and test bacterium co-cultures in a 96-well plate format to determine the absence or presence of antibacterial compound production. Our assay, called the bioluminescent simultaneous antagonism (BSLA) assay, can accurately distinguish between known antibacterial-producing and non-producing test bacteria. The BSLA assay was validated by screening 264 unknown soil isolates which resulted in the identification of 10 antibacterial-producing isolates, effectively decreasing the pool of isolates for downstream analysis by 96%. By design, the assay is simple and requires only general laboratory equipment; however, we have shown that the assay can be scaled to automated high-throughput screening systems. Taken together, the BSLA assay allows for the rapid pre-screening of unknown bacterial isolates which, when coupled with innovative downstream dereplication and identification technologies, can effectively fast-track antimicrobial discovery. Full article

(This article belongs to the Special Issue Advances in Novel Antibacterial Agents)

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Review

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13 pages, 855 KiB

Open AccessReview

An Exploratory Review of the Potential of Lytic Proteins and Bacteriophages for the Treatment of Tuberculosis

by Sibongile Mtimka, Priyen Pillay, Lusisizwe Kwezi, Ofentse Jacob Pooe and Tsepo Lebiletsa Tsekoa

Microorganisms 2024, 12(3), 570; https://doi.org/10.3390/microorganisms12030570 - 12 Mar 2024

Cited by 2 | Viewed by 2180

Abstract

Tuberculosis (TB) is a highly prevalent infectious disease that causes more than 1.5 million deaths a year. More than 25% of TB deaths occur in Africa, and TB is South Africa’s leading cause of death, with about 89,000 people dying of it yearly. [...] Read more.

Tuberculosis (TB) is a highly prevalent infectious disease that causes more than 1.5 million deaths a year. More than 25% of TB deaths occur in Africa, and TB is South Africa’s leading cause of death, with about 89,000 people dying of it yearly. The emergence of multidrug-resistant TB (MDR-TB) poses a significant threat to health security and could reverse the positive gains already made in the fight against TB. Antibiotic treatments are available, but side effects and the alarming increase in the prevalence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) will compromise the control of the spread and treatment of the disease. A promising option is to employ specialized enzymes encoded by bacteriophages, which destroy bacterial cell membranes and walls to treat tuberculosis. Phage therapy against bacteria is a known treatment that is now reemerging with lytic proteins. These proteins provide an alternative means to treat infectious diseases where conventional antibiotic regimens do not meet the requirements. This review explores and discusses the potential of lytic protein therapy as an antimicrobial strategy against M. tuberculosis and multidrug-resistant tuberculosis. Full article

(This article belongs to the Special Issue Advances in Novel Antibacterial Agents)

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22 pages, 420 KiB

Open AccessReview

Novel Beta Lactam Antibiotics for the Treatment of Multidrug-Resistant Gram-Negative Infections in Children: A Narrative Review

by Francesco Venuti, Lorenza Romani, Maia De Luca, Costanza Tripiciano, Paolo Palma, Maria Chiriaco, Andrea Finocchi and Laura Lancella

Microorganisms 2023, 11(7), 1798; https://doi.org/10.3390/microorganisms11071798 - 13 Jul 2023

Cited by 10 | Viewed by 3437

Abstract

Infections due to carbapenem-resistant Enterobacterales (CRE) are increasingly prevalent in children and are associated with poor clinical outcomes, especially in critically ill patients. Novel beta lactam antibiotics, including ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol, have been released in recent years to face the [...] Read more.

Infections due to carbapenem-resistant Enterobacterales (CRE) are increasingly prevalent in children and are associated with poor clinical outcomes, especially in critically ill patients. Novel beta lactam antibiotics, including ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol, have been released in recent years to face the emerging challenge of multidrug-resistant (MDR) Gram-negative bacteria. Nonetheless, several novel agents lack pediatric indications approved by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA), leading to uncertain pediatric-specific treatment strategies and uncertain dosing regimens in the pediatric population. In this narrative review we have summarized the available clinical and pharmacological data, current limitations and future prospects of novel beta lactam antibiotics in the pediatric population. Full article

(This article belongs to the Special Issue Advances in Novel Antibacterial Agents)

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