Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies, 2nd Volume

Topic Information

Dear Colleagues,

We have established one successful Topic on “Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies” with 61 papers, which encouraged us to open a second volume on the same topic. Please see the introduction about the Topic below. The rapid increase in antibiotic resistance raises concerns that we are returning to a pre-antibiotic era, in particular for Gram-negative infections; this is having an increasing impact on an international scale. There are few novel anti-Gram-negative/positive drugs being discovered and entering clinical trials, and therefore, novel drugs along with novel targets, techniques and methods that lead to new drugs are urgently needed. Overcoming resistance to restore the effectiveness of existing drugs or repurposing existing drugs are also important opportunities. This Special Issue is seeking original research articles and synopses (reviews) that demonstrate substantial advances within this field and we are inviting researchers from different fields (e.g., chemistry, biology, biochemistry, pharmacology, medicinal chemistry, PK PD modelers) 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 for human and animal use.

You are welcome to read the papers published in the first Topic:

“Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies”

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	4.8	5.5	2012	13.7 Days	CHF 2900
Applied Microbiology applmicrobiol	-	-	2021	13.3 Days	CHF 1000
Chemistry chemistry	2.1	2.5	2019	19.1 Days	CHF 1800
Molecules molecules	4.6	6.7	1996	14.6 Days	CHF 2700
Tropical Medicine and Infectious Disease tropicalmed	2.9	4.1	2016	19.4 Days	CHF 2700

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Published Papers (5 papers)

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All Antibiotics Applied Microbiology Chemistry Molecules TropicalMed

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19 pages, 2316 KiB  

Open AccessArticle

A New 4-Thiazolidinone Derivative (Les-6490) as a Gut Microbiota Modulator: Antimicrobial and Prebiotic Perspectives

by Yulian Konechnyi, Tetyana Rumynska, Ihor Yushyn, Serhii Holota, Vira Turkina, Mariana Ryviuk Rydel, Alicja Sękowska, Yuriy Salyha, Olena Korniychuk and Roman Lesyk

Antibiotics 2024, 13(4), 291; https://doi.org/10.3390/antibiotics13040291 - 22 Mar 2024

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Abstract

A novel 4-thiazolidinone derivative Les-6490 (pyrazol-4-thiazolidinone hybrid) was designed, synthesized, and characterized by spectral data. The compound was screened for its antimicrobial activity against some pathogenic bacteria and fungi and showed activity against Staphylococcus and Saccharomyces cerevisiae (the Minimum Inhibitory Concentration (MIC) 820 [...] Read more.

A novel 4-thiazolidinone derivative Les-6490 (pyrazol-4-thiazolidinone hybrid) was designed, synthesized, and characterized by spectral data. The compound was screened for its antimicrobial activity against some pathogenic bacteria and fungi and showed activity against Staphylococcus and Saccharomyces cerevisiae (the Minimum Inhibitory Concentration (MIC) 820 μM). The compound was studied in the rat adjuvant arthritis model (Freund’s Adjuvant) in vivo. Parietal and fecal microbial composition using 16S rRNA metagenome sequences was checked. We employed a range of analytical techniques, including Taxonomic Profiling (Taxa Analysis), Diversity Metrics (Alpha and Beta Diversity Analysis), Multivariate Statistical Methods (Principal Coordinates Analysis, Principal Component Analysis, Non-Metric Multidimensional Scaling), Clustering Analysis (Unweighted Pair-group Method with Arithmetic Mean), and Comparative Statistical Approaches (Community Differences Analysis, Between Group Variation Analysis, Metastat Analysis). The compound significantly impacted an increasing level of anti-inflammatory microorganisms (Blautia, Faecalibacterium prausnitzii, Succivibrionaceae, and Coriobacteriales) relative recovery of fecal microbiota composition. Anti-Treponemal activity in vivo was also noted. The tested compound Les-6490 has potential prebiotic activity with an indirect anti-inflammatory effect. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies, 2nd Volume)

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15 pages, 1778 KiB  

Open AccessArticle

Development of Novel Indole and Coumarin Derivatives as Antibacterial Agents That Target Histidine Kinase in S. aureus

by Lisha K. Poonacha, Rashmi Ramesh, Akshay Ravish, Arunkumar Mohan, Pradeep M. Uppar, Prashant K. Metri, Nanjunda Swamy Shivananju, Santosh L. Gaonkar, Shubha Gopal, Alexey Yu Sukhorukov, Vijay Pandey, Priya Babu Shubha and Basappa Basappa

Appl. Microbiol. 2023, 3(4), 1214-1228; https://doi.org/10.3390/applmicrobiol3040084 - 17 Oct 2023

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Abstract

Heterocyclic compounds can specifically regulate bacterial development by targeting specific bacterial enzymes and metabolic pathways. The ESKAPE pathogens are multidrug-resistant and cause nosocomial infections, which is one of the greatest challenges in clinical practice. The search for novel agents to combat resistant bacteria [...] Read more.

Heterocyclic compounds can specifically regulate bacterial development by targeting specific bacterial enzymes and metabolic pathways. The ESKAPE pathogens are multidrug-resistant and cause nosocomial infections, which is one of the greatest challenges in clinical practice. The search for novel agents to combat resistant bacteria has become one of the most important areas of antibacterial research today. Heterocyclic compounds offer a valuable strategy in the fight against resistance as they can be designed to interact with bacterial targets that are less prone to developing resistance mechanisms. Bacterial histidine kinases (HKs), which are a component of two-component bacterial systems, are a promising target for new antibacterial compounds. We have designed and synthesized novel indole derivatives as antibacterial agents. Among the series, indole-coumarin (4b) and bisindole (4e) have shown the best inhibitory activity against S. aureus. Further, in silico docking studies show that compounds 4b and 4e could target histidine kinases in bacteria. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies, 2nd Volume)

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20 pages, 7133 KiB  

Open AccessArticle

Virtual Screening of Potential RoxS Inhibitors and Evaluation of Their Antimicrobial Activity in Combination with Antibiotics against Clinically Resistant Bacteria

by Ya-Yan Huang, Jia-Hao Li, Ting-Ting Liang, Ze-An Zhao, Jun Xu and Wen-Ying Chen

Antibiotics 2023, 12(9), 1422; https://doi.org/10.3390/antibiotics12091422 - 08 Sep 2023

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Abstract

Pseudomonas aeruginosa with difficult-to-treat resistance has been designated as an urgent or serious threat by the CDC in the United States; therefore, novel antibacterial drugs and combination strategies are urgently needed. The sensor kinase RoxS is necessary for the aerobic growth of Pseudomonas [...] Read more.

Pseudomonas aeruginosa with difficult-to-treat resistance has been designated as an urgent or serious threat by the CDC in the United States; therefore, novel antibacterial drugs and combination strategies are urgently needed. The sensor kinase RoxS is necessary for the aerobic growth of Pseudomonas aeruginosa. This study aimed to screen candidate RoxS inhibitors and evaluate their efficacy in treating multi-drug-resistant and extensively drug-resistant Pseudomonas aeruginosa in combination with meropenem and amikacin to identify promising combination strategies. RoxS protein structures were constructed using homology modeling and potential RoxS inhibitors, including Ezetimibe, Deferasirox, and Posaconazole, were screened from the FDA-approved ZINC drug database using molecular docking and molecular dynamics simulations. MIC and checkerboard assays were used to determine the in vitro antimicrobial efficacy of the three drugs in combination with antibiotics. The results of in vitro experiments showed an additive effect of 100 μg/mL Deferasirox or 16 μg/mL Posaconazole in combination with meropenem and a synergistic effect of 1.5 μg/mL Deferasirox and amikacin. In summary, these three drugs are potential inhibitors of RoxS, and their combination with meropenem or amikacin is expected to reverse the resistance of P. aeruginosa, providing new combination strategies for the treatment of clinically difficult-to-treat Pseudomonas aeruginosa. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies, 2nd Volume)

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13 pages, 3387 KiB  

Open AccessArticle

Overcoming Drug Resistance in a Clinical C. albicans Strain Using Photoactivated Curcumin as an Adjuvant

by Carmen-Ecaterina Leferman, Laura Stoica, Mirela Tiglis, Bogdan Alexandru Stoica, Monica Hancianu, Alin Dumitru Ciubotaru, Delia Lidia Salaru, Aida Corina Badescu, Camelia-Margareta Bogdanici, Ioan-Adrian Ciureanu and Cristina-Mihaela Ghiciuc

Antibiotics 2023, 12(8), 1230; https://doi.org/10.3390/antibiotics12081230 - 25 Jul 2023

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Abstract

The limited antifungal drugs available and the rise of multidrug-resistant Candida species have made the efforts to improve antifungal therapies paramount. To this end, our research focused on the effect of a combined treatment between chemical and photodynamic therapy (PDT) towards a fluconazole-resistant [...] Read more.

The limited antifungal drugs available and the rise of multidrug-resistant Candida species have made the efforts to improve antifungal therapies paramount. To this end, our research focused on the effect of a combined treatment between chemical and photodynamic therapy (PDT) towards a fluconazole-resistant clinical Candida albicans strain. The co-treatment of PDT and curcumin in various doses with fluconazole (FLC) had an inhibitory effect on the growth of the FLC-resistant hospital strain of C. albicans in both difusimetric and broth microdilution methods. The proliferation of the cells was inhibited in the presence of curcumin at 3.125 µM and FLC at 41 µM concentrations. The possible involvement of oxidative stress was analyzed by adding menadione and glutathione as a prooxidant and antioxidant, respectively. In addition, we examined the photoactivated curcumin effect on efflux pumps, a mechanism often linked to drug resistance. Nile Red accumulation assays were used to evaluate efflux pumps activity through fluorescence microscopy and spectrofluorometry. The results showed that photoactivated curcumin at 3.125 µM inhibited the transport of the fluorescent substrate that cells usually expel, indicating its potential in combating drug resistance. Overall, the findings suggest that curcumin, particularly when combined with PDT, can effectively inhibit the growth of FLC-resistant C. albicans, addressing the challenge of yeast resistance to azole antifungals through upregulating multidrug transporters. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies, 2nd Volume)

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11 pages, 1393 KiB  

Open AccessArticle

Phentolamine Significantly Enhances Macrolide Antibiotic Antibacterial Activity against MDR Gram-Negative Bacteria

by Ze-Hua Cui, Hui-Ling He, Zi-Jian Zheng, Zhao-Qi Yuan, Ying Chen, Xin-Yi Huang, Hao Ren, Yu-Feng Zhou, Dong-Hao Zhao, Liang-Xing Fang, Yang Yu, Ya-Hong Liu, Xiao-Ping Liao and Jian Sun

Antibiotics 2023, 12(4), 760; https://doi.org/10.3390/antibiotics12040760 - 14 Apr 2023

Cited by 3 | Viewed by 1839

Abstract

Objectives: Multidrug-resistant (MDR) Gram-negative bacterial infections have limited treatment options due to the impermeability of the outer membrane. New therapeutic strategies or agents are urgently needed, and combination therapies using existing antibiotics are a potentially effective means to treat these infections. In this [...] Read more.

Objectives: Multidrug-resistant (MDR) Gram-negative bacterial infections have limited treatment options due to the impermeability of the outer membrane. New therapeutic strategies or agents are urgently needed, and combination therapies using existing antibiotics are a potentially effective means to treat these infections. In this study, we examined whether phentolamine can enhance the antibacterial activity of macrolide antibiotics against Gram-negative bacteria and investigated its mechanism of action. Methods: Synergistic effects between phentolamine and macrolide antibiotics were evaluated by checkerboard and time–kill assays and in vivo using a Galleria mellonella infection model. We utilized a combination of biochemical tests (outer membrane permeability, ATP synthesis, ΔpH gradient measurements, and EtBr accumulation assays) with scanning electron microscopy to clarify the mechanism of phentolamine enhancement of macrolide antibacterial activity against Escherichia coli. Results: In vitro tests of phentolamine combined with the macrolide antibiotics erythromycin, clarithromycin, and azithromycin indicated a synergistic action against E. coli test strains. The fractional concentration inhibitory indices (FICI) of 0.375 and 0.5 indicated a synergic effect that was consistent with kinetic time–kill assays. This synergy was also seen for Salmonella typhimurium, Klebsiella pneumoniae, and Actinobacter baumannii but not Pseudomonas aeruginosa. Similarly, a phentolamine/erythromycin combination displayed significant synergistic effects in vivo in the G. mellonella model. Phentolamine added singly to bacterial cells also resulted in direct outer membrane damage and was able to dissipate and uncouple membrane proton motive force from ATP synthesis that, resulted in enhanced cytoplasmic antibiotic accumulation via reduced efflux pump activity. Conclusions: Phentolamine potentiates macrolide antibiotic activity via reducing efflux pump activity and direct damage to the outer membrane leaflet of Gram-negative bacteria both in vitro and in vivo. Full article

(This article belongs to the Topic Novel Antimicrobial Agents: Discovery, Design and New Therapeutic Strategies, 2nd Volume)

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