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Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen Staphylococcus aureus

The emergence of multidrug resistance in the clinically significant pathogen Staphylococcus aureus is a global health burden, compounded by a diminishing drug development pipeline, and a lack of approved novel antimicrobials. Our previously reported first-in-class bacterial transcription inhibitors...

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Autores principales: Chu, Adrian Jun, Qiu, Yangyi, Harper, Rachel, Lin, Lin, Ma, Cong, Yang, Xiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461214/
https://www.ncbi.nlm.nih.gov/pubmed/32796751
http://dx.doi.org/10.3390/ijms21165772
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author Chu, Adrian Jun
Qiu, Yangyi
Harper, Rachel
Lin, Lin
Ma, Cong
Yang, Xiao
author_facet Chu, Adrian Jun
Qiu, Yangyi
Harper, Rachel
Lin, Lin
Ma, Cong
Yang, Xiao
author_sort Chu, Adrian Jun
collection PubMed
description The emergence of multidrug resistance in the clinically significant pathogen Staphylococcus aureus is a global health burden, compounded by a diminishing drug development pipeline, and a lack of approved novel antimicrobials. Our previously reported first-in-class bacterial transcription inhibitors “nusbiarylins” presented a promising prospect towards the discovery of novel antimicrobial agents with a novel mechanism. Here we investigated and characterised the lead nusbiarylin compound, MC4, and several of its chemical derivatives in both methicillin-resistant S. aureus (MRSA) and the S. aureus type strains, demonstrating their capacity for the arrest of growth and cellular respiration, impairment of RNA and intracellular protein levels at subinhibitory concentrations. In some instances, derivatives of MC4 were also shown to attenuate the production of staphylococcal virulence factors in vitro, such as the exoproteins α-toxin and Panton–Valentine Leukocidin (PVL). Trends observed from quantitative PCR assays suggested that nusbiarylins elicited these effects possibly by acting via but not limited to the modulation of global regulatory pathways, such as the agr regulon, which coordinates the expression of S. aureus genes associated with virulence. Our findings encourage the continued development of more potent compounds within this novel family of bacterial transcription inhibitors.
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spelling pubmed-74612142020-09-14 Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen Staphylococcus aureus Chu, Adrian Jun Qiu, Yangyi Harper, Rachel Lin, Lin Ma, Cong Yang, Xiao Int J Mol Sci Article The emergence of multidrug resistance in the clinically significant pathogen Staphylococcus aureus is a global health burden, compounded by a diminishing drug development pipeline, and a lack of approved novel antimicrobials. Our previously reported first-in-class bacterial transcription inhibitors “nusbiarylins” presented a promising prospect towards the discovery of novel antimicrobial agents with a novel mechanism. Here we investigated and characterised the lead nusbiarylin compound, MC4, and several of its chemical derivatives in both methicillin-resistant S. aureus (MRSA) and the S. aureus type strains, demonstrating their capacity for the arrest of growth and cellular respiration, impairment of RNA and intracellular protein levels at subinhibitory concentrations. In some instances, derivatives of MC4 were also shown to attenuate the production of staphylococcal virulence factors in vitro, such as the exoproteins α-toxin and Panton–Valentine Leukocidin (PVL). Trends observed from quantitative PCR assays suggested that nusbiarylins elicited these effects possibly by acting via but not limited to the modulation of global regulatory pathways, such as the agr regulon, which coordinates the expression of S. aureus genes associated with virulence. Our findings encourage the continued development of more potent compounds within this novel family of bacterial transcription inhibitors. MDPI 2020-08-11 /pmc/articles/PMC7461214/ /pubmed/32796751 http://dx.doi.org/10.3390/ijms21165772 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chu, Adrian Jun
Qiu, Yangyi
Harper, Rachel
Lin, Lin
Ma, Cong
Yang, Xiao
Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen Staphylococcus aureus
title Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen Staphylococcus aureus
title_full Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen Staphylococcus aureus
title_fullStr Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen Staphylococcus aureus
title_full_unstemmed Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen Staphylococcus aureus
title_short Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen Staphylococcus aureus
title_sort nusbiarylins inhibit transcription and target virulence factors in bacterial pathogen staphylococcus aureus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461214/
https://www.ncbi.nlm.nih.gov/pubmed/32796751
http://dx.doi.org/10.3390/ijms21165772
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