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Resistance of Gram-Positive Bacteria: Its Emergence, Mechanisms of Action and Treatment

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A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 16559

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Special Issue Editor

Dr. Jonathan Sellars

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Guest Editor

Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK
Interests: antibacterials; organic chemistry; antibiotic resistance; Mycobacterium tuberculosis; proteomics; drug discovery; assays
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Gram-positive bacteria are among the most common human pathogens associated with a clinical infection, ranging from mild skin infections to sepsis. Of great concern is the resistance of these bacteria to antimicrobial agents, in particular to methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).

Consequently, with the ever-increasing threat posed by antibiotic resistance, demand for new strategies to prevent and treat infection is of paramount importance. Moreover, understanding the underlying mechanisms of resistance provides invaluable information for drug development, selectivity and the reduction of off-target toxicity.

This Special Issue aims to update the current knowledge surrounding the development of resistance in Gram-positive bacteria from a systems biology perspective down to the individual enzymes responsible. Alongside this, the issue will bring together the current knowledge surrounding the development of new treatment strategies for the prevention and treatment of resistant bacterial infections.

Dr. Jonathan Sellars
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

Gram-positive
Actinomycetes
Streptococcus
Staphylococcus Mechanism of resistance
Drug discovery
Antibiotic resistance Systems biology
Drug development

Published Papers (4 papers)

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Research

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23 pages, 7680 KiB

Open AccessArticle

Antimicrobial Activity of Nitrogen-Containing 5-α-Androstane Derivatives: In Silico and Experimental Studies

by Lela Amiranashvili, Nanuli Nadaraia, Maia Merlani, Charalampos Kamoutsis, Anthi Petrou, Athina Geronikaki, Pavel Pogodin, Dmitry Druzhilovskiy, Vladimir Poroikov, Ana Ciric, Jasmina Glamočlija and Marina Sokovic

Antibiotics 2020, 9(5), 224; https://doi.org/10.3390/antibiotics9050224 - 30 Apr 2020

Cited by 13 | Viewed by 3240

Abstract

We evaluated the antimicrobial activity of thirty-one nitrogen-containing 5-α-androstane derivatives in silico using computer program PASS (Prediction of Activity Spectra for Substances) and freely available PASS-based web applications (such as Way2Drug). Antibacterial activity was predicted for 27 out of 31 molecules; antifungal activity was predicted for 25 out of 31 compounds. The results of experiments, which we conducted to study the antimicrobial activity, are in agreement with the predictions. All compounds were found to be active with MIC (Minimum Inhibitory Concentration) and MBC (Minimum Bactericidal Concentration) values in the range of 0.0005–0.6 mg/mL. The activity of all studied 5-α-androstane derivatives exceeded or was equal to those of Streptomycin and, except for the 3β-hydroxy-17α-aza-d-homo-5α-androstane-17-one, all molecules were more active than Ampicillin. Activity against the resistant strains of E. coli, P. aeruginosa, and methicillin-resistant Staphylococcus aureus was also shown in experiments. Antifungal activity was determined with MIC and MFC (Minimum Fungicidal Concentration) values varying from 0.007 to 0.6 mg/mL. Most of the compounds were found to be more potent than the reference drugs Bifonazole and Ketoconazole. According to the results of docking studies, the putative targets for antibacterial and antifungal activity are UDP-N-acetylenolpyruvoylglucosamine reductase and 14-α-demethylase, respectively. In silico assessments of the acute rodent toxicity and cytotoxicity obtained using GUSAR (General Unrestricted Structure-Activity Relationships) and CLC-Pred (Cell Line Cytotoxicity Predictor) web-services were low for the majority of compounds under study, which contributes to the chances for those compounds to advance in the development. Full article

(This article belongs to the Special Issue Resistance of Gram-Positive Bacteria: Its Emergence, Mechanisms of Action and Treatment)

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10 pages, 251 KiB

Open AccessArticle

Plasticity of Coagulase-Negative Staphylococcal Membrane Fatty Acid Composition and Implications for Responses to Antimicrobial Agents

by Kiran B. Tiwari, Craig Gatto and Brian J. Wilkinson

Antibiotics 2020, 9(5), 214; https://doi.org/10.3390/antibiotics9050214 - 28 Apr 2020

Cited by 12 | Viewed by 2491

Abstract

Staphylococcus aureus demonstrates considerable membrane lipid plasticity in response to different growth environments, which is of potential relevance to response and resistance to various antimicrobial agents. This information is not available for various species of coagulase-negative staphylococci, which are common skin inhabitants, can be significant human pathogens, and are resistant to multiple antibiotics. We determined the total fatty acid compositions of Staphylococcus auricularis, Staphylococcus capitis, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, and Staphylococcus aureus for comparison purposes. Different proportions of branched-chain and straight-chain fatty acids were observed amongst the different species. However, growth in cation-supplemented Mueller–Hinton broth significantly increased the proportion of branched-chain fatty acids, and membrane fluidities as measured by fluorescence anisotropy. Cation-supplemented Mueller–Hinton broth is used for routine determination of antimicrobial susceptibilities. Growth in serum led to significant increases in straight-chain unsaturated fatty acids in the total fatty acid profiles, and decreases in branched-chain fatty acids. This indicates preformed fatty acids can replace biosynthesized fatty acids in the glycerolipids of coagulase-negative staphylococci, and indicates that bacterial fatty acid biosynthesis system II may not be a good target for antimicrobial agents in these organisms. Even though the different species are expected to be exposed to skin antimicrobial fatty acids, they were susceptible to the major skin antimicrobial fatty acid sapienic acid (C16:1Δ6). Certain species were not susceptible to linoleic acid (C18:2Δ9,12), but no obvious relationship to fatty acid composition could be discerned. Full article

(This article belongs to the Special Issue Resistance of Gram-Positive Bacteria: Its Emergence, Mechanisms of Action and Treatment)

20 pages, 2292 KiB

Open AccessArticle

Advanced Resistance Studies Identify Two Discrete Mechanisms in Staphylococcus aureus to Overcome Antibacterial Compounds that Target Biotin Protein Ligase

by Andrew J. Hayes, Jiulia Satiaputra, Louise M. Sternicki, Ashleigh S. Paparella, Zikai Feng, Kwang J. Lee, Beatriz Blanco-Rodriguez, William Tieu, Bart A. Eijkelkamp, Keith E. Shearwin, Tara L. Pukala, Andrew D. Abell, Grant W. Booker and Steven W. Polyak

Antibiotics 2020, 9(4), 165; https://doi.org/10.3390/antibiotics9040165 - 06 Apr 2020

Cited by 3 | Viewed by 3569

Abstract

Biotin protein ligase (BPL) inhibitors are a novel class of antibacterial that target clinically important methicillin-resistant Staphylococcus aureus (S. aureus). In S. aureus, BPL is a bifunctional protein responsible for enzymatic biotinylation of two biotin-dependent enzymes, as well as serving as a transcriptional repressor that controls biotin synthesis and import. In this report, we investigate the mechanisms of action and resistance for a potent anti-BPL, an antibacterial compound, biotinyl-acylsulfamide adenosine (BASA). We show that BASA acts by both inhibiting the enzymatic activity of BPL in vitro, as well as functioning as a transcription co-repressor. A low spontaneous resistance rate was measured for the compound (<10⁻⁹) and whole-genome sequencing of strains evolved during serial passaging in the presence of BASA identified two discrete resistance mechanisms. In the first, deletion of the biotin-dependent enzyme pyruvate carboxylase is proposed to prioritize the utilization of bioavailable biotin for the essential enzyme acetyl-CoA carboxylase. In the second, a D200E missense mutation in BPL reduced DNA binding in vitro and transcriptional repression in vivo. We propose that this second resistance mechanism promotes bioavailability of biotin by derepressing its synthesis and import, such that free biotin may outcompete the inhibitor for binding BPL. This study provides new insights into the molecular mechanisms governing antibacterial activity and resistance of BPL inhibitors in S. aureus. Full article

(This article belongs to the Special Issue Resistance of Gram-Positive Bacteria: Its Emergence, Mechanisms of Action and Treatment)

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Review

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23 pages, 2126 KiB

Open AccessReview

Detection of Quorum-Sensing Molecules for Pathogenic Molecules Using Cell-Based and Cell-Free Biosensors

by Craig Miller and Jordon Gilmore

Antibiotics 2020, 9(5), 259; https://doi.org/10.3390/antibiotics9050259 - 16 May 2020

Cited by 28 | Viewed by 6529

Abstract

Since the discovery and subsequent use of penicillin, antibiotics have been used to treat most bacterial infections in the U.S. Over time, the repeated prescription of many antibiotics has given rise to many antibiotic-resistant microbes. A bacterial strain becomes resistant by horizontal gene transfer, where surviving microbes acquire genetic material or DNA fragments from adjacent bacteria that encode for resistance. In order to avoid significant bacterial resistance, novel and target therapeutics are needed. Further advancement of diagnostic technologies could be used to develop novel treatment strategies. The use of biosensors to detect quorum-sensing signaling molecules has the potential to provide timely diagnostic information toward mitigating the multidrug-resistant bacteria epidemic. Resistance and pathogenesis are controlled by quorum-sensing (QS) circuits. QS systems secrete or passively release signaling molecules when the bacterial concentration reaches a certain threshold. Signaling molecules give an early indication of virulence. Detection of these compounds in vitro or in vivo can be used to identify the onset of infection. Whole-cell and cell-free biosensors have been developed to detect quorum-sensing signaling molecules. This review will give an overview of quorum networks in the most common pathogens found in chronic and acute infections. Additionally, the current state of research surrounding the detection of quorum-sensing molecules will be reviewed. Followed by a discussion of future works toward the advancement of technologies to quantify quorum signaling molecules in chronic and acute infections. Full article

(This article belongs to the Special Issue Resistance of Gram-Positive Bacteria: Its Emergence, Mechanisms of Action and Treatment)

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