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Antibiotics
Special Issues
Design and Preparation of Antimicrobial Agents
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Design and Preparation of Antimicrobial Agents

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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 33347

Special Issue Editor

Dr. Martina Hrast

E-Mail Website
Guest Editor
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Interests: design and synthesis of low molecular inhibitors; inhibitors of bacterial cell wall; Mur enzymes; penicillin binding proteins; InhA inhibitors; DNA girase inhibitors; FtsZ inhibitors; enzymatic and antibacterial evaluation of compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The inappropriate use and misuse of antibacterial agents led to the emergence of (multi)resistant bacterial strains that represent one of the biggest threats to public health. Several common infections, such as gonorrhea, pneumonia, and tuberculosis are very hard or almost impossible to cure with the current arsenal of antibacterial agents. Therefore, there is an urgent need for the research and development of new antibiotics. There are numerous different methods to design new antibacterial agents, i.e., (i) the structural modification of known antibiotics to avoid the bacterial resistance mechanism; (ii) the development of compounds that inhibit the mechanism of resistance to antibiotics; (iii) new antibacterial agents with novel mechanisms of action; (iv) new compounds that in combination with (inefficient) antibacterial drugs restore the effect of these drugs (e.g., efflux pump inhibitors); (v) new modern approaches, such as inhibitors of virulence factors, nanoparticles, antimicrobial peptides, phage therapy, and antisense oligonucleotides.

This Special Issue will publish the most recent research in the design and preparation of new antibacterial agents with potential use in human or veterinary medicine. Therefore, we invite authors to submit original research papers or reviews covering all aspects of this thematic issue.

Dr. Martina Hrast
Guest Editor

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

  • new antimicrobial agents
  • drug design
  • synthesis of new antibacterial drugs
  • computational chemistry
  • drug repurposing
  • novel mechanism of antibacterial action

Published Papers (12 papers)

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Editorial

Jump to: Research, Review

4 pages, 196 KiB  
Editorial
Design and Preparation of Antimicrobial Agents
by Martina Hrast
Antibiotics 2022, 11(12), 1778; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11121778 - 08 Dec 2022
Cited by 1 | Viewed by 848
Abstract
Improper use and misuse of antibacterial agents have led to the emergence of (multi)resistant bacterial strains, which are 1 of the top-10 public-health threats, according to the WHO [...] Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)

Research

Jump to: Editorial, Review

22 pages, 2014 KiB  
Article
New MraYAA Inhibitors with an Aminoribosyl Uridine Structure and an Oxadiazole
by Hongwei Wan, Raja Ben Othman, Laurent Le Corre, Mélanie Poinsot, Martin Oliver, Ana Amoroso, Bernard Joris, Thierry Touzé, Rodolphe Auger, Sandrine Calvet-Vitale, Michaël Bosco and Christine Gravier-Pelletier
Antibiotics 2022, 11(9), 1189; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11091189 - 02 Sep 2022
Cited by 2 | Viewed by 1606
Abstract
New inhibitors of the bacterial transferase MraY from Aquifex aeolicus (MraYAA), based on the aminoribosyl uridine central core of known natural MraY inhibitors, have been designed to generate interaction of their oxadiazole linker with the key amino acids (H324 or H325) [...] Read more.
New inhibitors of the bacterial transferase MraY from Aquifex aeolicus (MraYAA), based on the aminoribosyl uridine central core of known natural MraY inhibitors, have been designed to generate interaction of their oxadiazole linker with the key amino acids (H324 or H325) of the enzyme active site, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin. A panel of ten compounds was synthetized notably thanks to a robust microwave-activated one-step sequence for the synthesis of the oxadiazole ring that involved the O-acylation of an amidoxime and subsequent cyclization. The synthetized compounds, with various hydrophobic substituents on the oxadiazole ring, were tested against the MraYAA transferase activity. Although with poor antibacterial activity, nine out of the ten compounds revealed the inhibition of the MraYAA activity in the range of 0.8 µM to 27.5 µM. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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12 pages, 1623 KiB  
Article
Identification of Novel Inhibitor of Enoyl-Acyl Carrier Protein Reductase (InhA) Enzyme in Mycobacterium tuberculosis from Plant-Derived Metabolites: An In Silico Study
by Kratika Singh, Niharika Pandey, Firoz Ahmad, Tarun Kumar Upadhyay, Mohammad Hayatul Islam, Nawaf Alshammari, Mohd Saeed, Lamya Ahmed Al-Keridis and Rolee Sharma
Antibiotics 2022, 11(8), 1038; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11081038 - 01 Aug 2022
Cited by 8 | Viewed by 2799
Abstract
Mycobacterium tuberculosis (M.tb.) enoyl-acyl carrier protein (ACP) reductase (InhA) is validated as a useful target for tuberculosis therapy and is considered an attractive enzyme to drug discovery. This study aimed to identify the novel inhibitor of the InhA enzyme, a potential [...] Read more.
Mycobacterium tuberculosis (M.tb.) enoyl-acyl carrier protein (ACP) reductase (InhA) is validated as a useful target for tuberculosis therapy and is considered an attractive enzyme to drug discovery. This study aimed to identify the novel inhibitor of the InhA enzyme, a potential target of M.tb. involved in the type II fatty acid biosynthesis pathway that controls mycobacterial cell envelope synthesis. We compiled 80 active compounds from Ruta graveolens and citrus plants belonging to the Rutaceae family for pharmacokinetics and molecular docking analyses. The chemical structures of the 80 phytochemicals and the 3D structure of the target protein were retrieved from the PubChem database and RCSB Protein Data Bank, respectively. The evaluation of druglikeness was performed based on Lipinski’s Rule of Five, while the computed phytochemical properties and molecular descriptors were used to predict the ADMET of the compounds. Amongst these, 11 pharmacokinetically-screened compounds were further examined by performing molecular docking analysis with an InhA target using AutoDock 4.2. The docking results showed that gravacridonediol, a major glycosylated natural alkaloid from Ruta graveolens, might possess a promising inhibitory potential against InhA, with a binding energy (B.E.) of −10.80 kcal/mole and inhibition constant (Ki) of 600.24 nM. These contrast those of the known inhibitor triclosan, which has a B.E. of −6.69 kcal/mole and Ki of 12.43 µM. The binding efficiency of gravacridonediol was higher than that of the well-known inhibitor triclosan against the InhA target. The present study shows that the identified natural compound gravacridonediol possesses drug-like properties and also holds promise in inhibiting InhA, a key target enzyme of M.tb. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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20 pages, 4836 KiB  
Article
Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives
by Katharigatta N. Venugopala, Nizar A. Al-Shar’i, Lina A. Dahabiyeh, Wafa Hourani, Pran Kishore Deb, Melendhran Pillay, Bashaer Abu-Irmaileh, Yasser Bustanji, Sandeep Chandrashekharappa, Christophe Tratrat, Mahesh Attimarad, Anroop B. Nair, Nagaraja Sreeharsha, Pottathil Shinu, Michelyne Haroun, Mahmoud Kandeel, Abdulmalek Ahmed Balgoname, Rashmi Venugopala and Mohamed A. Morsy
Antibiotics 2022, 11(7), 831; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11070831 - 21 Jun 2022
Cited by 6 | Viewed by 2304
Abstract
A series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a–3m) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to [...] Read more.
A series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a–3m) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv. Compound 3k with an imidazole ring at the 2-position of the dihydroquinazolin-4(1H)-one also showed significant inhibitory action against both the susceptible strain H37Rv and MDR strains with MIC values of 4 and 16 µg/mL, respectively. The computational results revealed the mycobacterial pyridoxal-5′-phosphate (PLP)-dependent aminotransferase (BioA) enzyme as the potential target for the tested compounds. In vitro, ADMET calculations and cytotoxicity studies against the normal human dermal fibroblast cells indicated the safety and tolerability of the test compounds 3k–3m. Thus, compounds 3k–3m warrant further optimization to develop novel BioA inhibitors for the treatment of drug-sensitive H37Rv and drug-resistant MTB. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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16 pages, 7461 KiB  
Article
Computational Development of Inhibitors of Plasmid-Borne Bacterial Dihydrofolate Reductase
by Pedro J. Silva
Antibiotics 2022, 11(6), 779; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11060779 - 07 Jun 2022
Cited by 1 | Viewed by 1773
Abstract
Resistance to trimethoprim and other antibiotics targeting dihydrofolate reductase may arise in bacteria harboring an atypical, plasmid-encoded, homotetrameric dihydrofolate reductase, called R67 DHFR. Although developing inhibitors to this enzyme may be expected to be promising drugs to fight trimethoprim-resistant strains, there is a [...] Read more.
Resistance to trimethoprim and other antibiotics targeting dihydrofolate reductase may arise in bacteria harboring an atypical, plasmid-encoded, homotetrameric dihydrofolate reductase, called R67 DHFR. Although developing inhibitors to this enzyme may be expected to be promising drugs to fight trimethoprim-resistant strains, there is a paucity of reports describing the development of such molecules. In this manuscript, we describe the design of promising lead compounds to target R67 DHFR. Density-functional calculations were first used to identify the modifications of the pterin core that yielded derivatives likely to bind the enzyme and not susceptible to being acted upon by it. These unreactive molecules were then docked to the active site, and the stability of the docking poses of the best candidates was analyzed through triplicate molecular dynamics simulations, and compared to the binding stability of the enzyme–substrate complex. Molecule 32 ([6-(methoxymethyl)-4-oxo-3,7-dihydro-4H-pyrano[2,3-d]pyrimidin-2-yl]methyl-guanidinium) was shown by this methodology to afford extremely stable binding towards R67 DHFR and to prevent simultaneous binding to the substrate. Additional docking and molecular dynamics simulations further showed that this candidate also binds strongly to the canonical prokaryotic dihydrofolate reductase and to human DHFR, and is therefore likely to be useful to the development of chemotherapeutic agents and of dual-acting antibiotics that target the two types of bacterial dihydrofolate reductase. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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24 pages, 4987 KiB  
Article
An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate Pathway
by Rok Frlan
Antibiotics 2022, 11(5), 675; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics11050675 - 17 May 2022
Cited by 4 | Viewed by 2415
Abstract
Enzymes belonging to the shikimate pathway have long been considered promising targets for antibacterial drugs because they have no counterpart in mammals and are essential for bacterial growth and virulence. However, despite decades of research, there are currently no clinically relevant antibacterial drugs [...] Read more.
Enzymes belonging to the shikimate pathway have long been considered promising targets for antibacterial drugs because they have no counterpart in mammals and are essential for bacterial growth and virulence. However, despite decades of research, there are currently no clinically relevant antibacterial drugs targeting any of these enzymes, and there are legitimate concerns about whether they are sufficiently druggable, i.e., whether they can be adequately modulated by small and potent drug-like molecules. In the present work, in silico analyses combining evolutionary conservation and druggability are performed to determine whether these enzymes are candidates for broad-spectrum antibacterial therapy. The results presented here indicate that the substrate-binding sites of most enzymes in this pathway are suitable drug targets because of their reasonable conservation and druggability scores. An exception was the substrate-binding site of 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase, which was found to be undruggable because of its high content of charged residues and extremely high overall polarity. Although the presented study was designed from the perspective of broad-spectrum antibacterial drug development, this workflow can be readily applied to any antimicrobial target analysis, whether narrow- or broad-spectrum. Moreover, this research also contributes to a deeper understanding of these enzymes and provides valuable insights into their properties. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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16 pages, 9127 KiB  
Article
Analysis of Plant Origin Antibiotics against Oral Bacterial Infections Using In Vitro and In Silico Techniques and Characterization of Active Constituents
by Abdul Rafey, Adnan Amin, Muhammad Kamran, Uzma Haroon, Kainat Farooq, Kenn Foubert and Luc Pieters
Antibiotics 2021, 10(12), 1504; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10121504 - 08 Dec 2021
Cited by 10 | Viewed by 2753
Abstract
The pervasiveness of oral bacterial infections in diabetic patients is a serious health concern that may produce severe complications. We investigated 26 Ayurvedic medicinal plants traditionally used for treatment of the oral bacterial infections with the aim to look for new promising drug [...] Read more.
The pervasiveness of oral bacterial infections in diabetic patients is a serious health concern that may produce severe complications. We investigated 26 Ayurvedic medicinal plants traditionally used for treatment of the oral bacterial infections with the aim to look for new promising drug leads that can be further employed for herbal formulation design. The plants were grouped into three categories based on traditional usage. All plant extracts were examined for antibacterial, antibiofilm and antiquorum-sensing properties. The plants with significant activities including Juglans regia, Syzygium aromaticum, Eruca sativa, Myristica fragrans, Punica granatum and Azadirachta indica were further analyzed using HPLC-DAD-QToF and GC-MS. In silico and in vitro activity was evaluated for selected constituents. Finally, it could be concluded that eugenol and 2-phenylethylisothiocyanate are major contributors towards inhibition of bacterial biofilms and quorum sensing. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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18 pages, 1788 KiB  
Article
Effect of Ursolic and Oleanolic Acids on Lipid Membranes: Studies on MRSA and Models of Membranes
by Sandrine Verstraeten, Lucy Catteau, Laila Boukricha, Joelle Quetin-Leclercq and Marie-Paule Mingeot-Leclercq
Antibiotics 2021, 10(11), 1381; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10111381 - 11 Nov 2021
Cited by 9 | Viewed by 2431
Abstract
Staphylococcus aureus is an opportunistic pathogen and the major causative agent of life-threatening hospital- and community-acquired infections. A combination of antibiotics could be an opportunity to address the widespread emergence of antibiotic-resistant strains, including Methicillin-Resistant S. aureus (MRSA). We here investigated the potential [...] Read more.
Staphylococcus aureus is an opportunistic pathogen and the major causative agent of life-threatening hospital- and community-acquired infections. A combination of antibiotics could be an opportunity to address the widespread emergence of antibiotic-resistant strains, including Methicillin-Resistant S. aureus (MRSA). We here investigated the potential synergy between ampicillin and plant-derived antibiotics (pentacyclic triterpenes, ursolic acid (UA) and oleanolic acid (OA)) towards MRSA (ATCC33591 and COL) and the mechanisms involved. We calculated the Fractional Inhibitory Concentration Index (FICI) and demonstrated synergy. We monitored fluorescence of Bodipy-TR-Cadaverin, propidium iodide and membrane potential-sensitive probe for determining the ability of UA and OA to bind to lipoteichoic acids (LTA), and to induce membrane permeabilization and depolarization, respectively. Both pentacyclic triterpenes were able to bind to LTA and to induce membrane permeabilization and depolarization in a dose-dependent fashion. These effects were not accompanied by significant changes in cellular concentration of pentacyclic triterpenes and/or ampicillin, suggesting an effect mediated through lipid membranes. We therefore focused on membranous effects induced by UA and OA, and we investigated on models of membranes, the role of specific lipids including phosphatidylglycerol and cardiolipin. The effect induced on membrane fluidity, permeability and ability to fuse were studied by determining changes in fluorescence anisotropy of DPH/generalized polarization of Laurdan, calcein release from liposomes, fluorescence dequenching of octadecyl-rhodamine B and liposome-size, respectively. Both UA and OA showed a dose-dependent effect with membrane rigidification, increase of membrane permeabilization and fusion. Except for the effect on membrane fluidity, the effect of UA was consistently higher compared with that obtained with OA, suggesting the role of methyl group position. All together the data demonstrated the potential role of compounds acting on lipid membranes for enhancing the activity of other antibiotics, like ampicillin and inducing synergy. Such combinations offer an opportunity to explore a larger antibiotic chemical space. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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17 pages, 3230 KiB  
Article
Novel Bifunctional Acylase from Actinoplanes utahensis: A Versatile Enzyme to Synthesize Antimicrobial Compounds and Use in Quorum Quenching Processes
by Lara Serrano-Aguirre, Rodrigo Velasco-Bucheli, Begoña García-Álvarez, Ana Saborido, Miguel Arroyo and Isabel de la Mata
Antibiotics 2021, 10(8), 922; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10080922 - 29 Jul 2021
Cited by 6 | Viewed by 3429
Abstract
Many intercellular communication processes, known as quorum sensing (QS), are regulated by the autoinducers N-acyl-l-homoserine lactones (AHLs) in Gram-negative bacteria. The inactivation of these QS processes using different quorum quenching (QQ) strategies, such as enzymatic degradation of the autoinducers or [...] Read more.
Many intercellular communication processes, known as quorum sensing (QS), are regulated by the autoinducers N-acyl-l-homoserine lactones (AHLs) in Gram-negative bacteria. The inactivation of these QS processes using different quorum quenching (QQ) strategies, such as enzymatic degradation of the autoinducers or the receptor blocking with non-active analogs, could be the basis for the development of new antimicrobials. This study details the heterologous expression, purification, and characterization of a novel N-acylhomoserine lactone acylase from Actinoplanes utahensis NRRL 12052 (AuAHLA), which can hydrolyze different natural penicillins and N-acyl-homoserine lactones (with or without 3-oxo substitution), as well as synthesize them. Kinetic parameters for the hydrolysis of a broad range of substrates have shown that AuAHLA prefers penicillin V, followed by C12-HSL. In addition, AuAHLA inhibits the production of violacein by Chromobacterium violaceum CV026, confirming its potential use as a QQ agent. Noteworthy, AuAHLA is also able to efficiently synthesize penicillin V, besides natural AHLs and phenoxyacetyl-homoserine lactone (POHL), a non-natural analog of AHLs that could be used to block QS receptors and inhibit signal of autoinducers, being the first reported AHL acylase capable of synthesizing AHLs. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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30 pages, 6960 KiB  
Article
A Fine-Tuned Lipophilicity/Hydrophilicity Ratio Governs Antibacterial Potency and Selectivity of Bifurcated Halogen Bond-Forming NBTIs
by Anja Kolarič, Maja Kokot, Martina Hrast, Matjaž Weiss, Irena Zdovc, Jurij Trontelj, Simon Žakelj, Marko Anderluh and Nikola Minovski
Antibiotics 2021, 10(7), 862; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10070862 - 15 Jul 2021
Cited by 11 | Viewed by 5015
Abstract
Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against [...] Read more.
Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against some of the most concerning hard-to-treat pathogens for which new antibacterials are urgently needed, as reported by the WHO and CDC. NBTIs enzyme activity and whole cell potency seems to depend on the fine-tuned lipophilicity/hydrophilicity ratio that governs the permeability of those compounds through the bacterial membranes. Lipophilicity of NBTIs is apparently optimal for passing through the membrane of Gram-positive bacteria, but the higher, although not excessive lipophilicity and suitable hydrophilicity seems to determine the passage through Gram-negative bacterial membranes. However, due to the considerable hERG inhibition, which is still at least two orders of magnitude away from MICs, continued optimization is required to realize their full potential. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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21 pages, 11052 KiB  
Article
Triazolo Based-Thiadiazole Derivatives. Synthesis, Biological Evaluation and Molecular Docking Studies
by Charalampos Kamoutsis, Maria Fesatidou, Anthi Petrou, Athina Geronikaki, Vladimir Poroikov, Marija Ivanov, Marina Soković, Ana Ćirić, Alejandro Carazo and Přemysl Mladěnka
Antibiotics 2021, 10(7), 804; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10070804 - 02 Jul 2021
Cited by 21 | Viewed by 3035
Abstract
The goal of this research is to investigate the antimicrobial activity of nineteen previously synthesized 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives. The compounds were tested against a panel of three Gram-positive and three Gram-negative bacteria, three resistant strains, and six fungi. Minimal inhibitory, bactericidal, and fungicidal concentrations [...] Read more.
The goal of this research is to investigate the antimicrobial activity of nineteen previously synthesized 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives. The compounds were tested against a panel of three Gram-positive and three Gram-negative bacteria, three resistant strains, and six fungi. Minimal inhibitory, bactericidal, and fungicidal concentrations were determined by a microdilution method. All of the compounds showed antibacterial activity that was more potent than both reference drugs, ampicillin and streptomycin, against all bacteria tested. Similarly, they were also more active against resistant bacterial strains. The antifungal activity of the compounds was up to 80-fold higher than ketoconazole and from 3 to 40 times higher than bifonazole, both of which were used as reference drugs. The most active compounds (2, 3, 6, 7, and 19) were tested for their inhibition of P. aeruginosa biofilm formation. Among them, compound 3 showed significantly higher antibiofilm activity and appeared to be equipotent with ampicillin. The prediction of the probable mechanism by docking on antibacterial targets revealed that E. coli MurB is the most suitable enzyme, while docking studies on antifungal targets indicated a probable involvement of CYP51 in the mechanism of antifungal activity. Finally, the toxicity testing in human cells confirmed their low toxicity both in cancerous cell line MCF7 and non-cancerous cell line HK-2. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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Review

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12 pages, 5128 KiB  
Review
The Role of Staphylococcus aureus YycFG in Gene Regulation, Biofilm Organization and Drug Resistance
by Shizhou Wu, Junqi Zhang, Qi Peng, Yunjie Liu, Lei Lei and Hui Zhang
Antibiotics 2021, 10(12), 1555; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10121555 - 19 Dec 2021
Cited by 18 | Viewed by 3335
Abstract
Antibiotic resistance is a serious global health concern that may have significant social and financial consequences. Methicillin-resistant Staphylococcus aureus (MRSA) infection is responsible for substantial morbidity and leads to the death of 21.8% of infected patients annually. A lack of novel antibiotics has [...] Read more.
Antibiotic resistance is a serious global health concern that may have significant social and financial consequences. Methicillin-resistant Staphylococcus aureus (MRSA) infection is responsible for substantial morbidity and leads to the death of 21.8% of infected patients annually. A lack of novel antibiotics has prompted the exploration of therapies targeting bacterial virulence mechanisms. The two-component signal transduction system (TCS) enables microbial cells to regulate gene expression and the subsequent metabolic processes that occur due to environmental changes. The YycFG TCS in S. aureus is essential for bacterial viability, the regulation of cell membrane metabolism, cell wall synthesis and biofilm formation. However, the role of YycFG-associated biofilm organization in S. aureus antimicrobial drug resistance and gene regulation has not been discussed in detail. We reviewed the main molecules involved in YycFG-associated cell wall biosynthesis, biofilm development and polysaccharide intercellular adhesin (PIA) accumulation. Two YycFG-associated regulatory mechanisms, accessory gene regulator (agr) and staphylococcal accessory regulator (SarA), were also discussed. We highlighted the importance of biofilm formation in the development of antimicrobial drug resistance in S. aureus infections. Data revealed that inhibition of the YycFG pathway reduced PIA production, biofilm formation and bacterial pathogenicity, which provides a potential target for the management of MRSA-induced infections. Full article
(This article belongs to the Special Issue Design and Preparation of Antimicrobial Agents)
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