The Response Regulator BfmR Is a Potential Drug Target for <named-content content-type="genus-species">Acinetobacter baumannii</named-content>

ABSTRACT Identification and validation is the first phase of target-based antimicrobial development. BfmR (RstA), a response regulator in a two-component signal transduction system (TCS) in Acinetobacter baumannii, is an intriguing potential antimicrobial target. A unique characteristic of BfmR is t...

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Autores principales:	Thomas A. Russo, Akshay Manohar, Janet M. Beanan, Ruth Olson, Ulrike MacDonald, Jessica Graham, Timothy C. Umland
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Acinetobacter baumannii Gram-negative bacilli antibiotic target bacterial drug target drug discovery essential genes Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0bbb530e852f461ea2681f39154ed515
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spelling	oai:doaj.org-article:0bbb530e852f461ea2681f39154ed5152021-11-15T15:21:17ZThe Response Regulator BfmR Is a Potential Drug Target for <named-content content-type="genus-species">Acinetobacter baumannii</named-content>10.1128/mSphere.00082-162379-5042https://doaj.org/article/0bbb530e852f461ea2681f39154ed5152016-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00082-16https://doaj.org/toc/2379-5042ABSTRACT Identification and validation is the first phase of target-based antimicrobial development. BfmR (RstA), a response regulator in a two-component signal transduction system (TCS) in Acinetobacter baumannii, is an intriguing potential antimicrobial target. A unique characteristic of BfmR is that its inhibition would have the dual benefit of significantly decreasing in vivo survival and increasing sensitivity to selected antimicrobials. Studies on the clinically relevant strain AB307-0294 have shown BfmR to be essential in vivo. Here, we demonstrate that this phenotype in strains AB307-0294 and AB908 is mediated, in part, by enabling growth in human ascites fluid and serum. Further, BfmR conferred resistance to complement-mediated bactericidal activity that was independent of capsular polysaccharide. Importantly, BfmR also increased resistance to the clinically important antimicrobials meropenem and colistin. BfmR was highly conserved among A. baumannii strains. The crystal structure of the receiver domain of BfmR was determined, lending insight into putative ligand binding sites. This enabled an in silico ligand binding analysis and a blind docking strategy to assess use as a potential druggable target. Predicted binding hot spots exist at the homodimer interface and the phosphorylation site. These data support pursuing the next step in the development process, which includes determining the degree of inhibition needed to impact growth/survival and the development a BfmR activity assay amenable to high-throughput screening for the identification of inhibitors. Such agents would represent a new class of antimicrobials active against A. baumannii which could be active against other Gram-negative bacilli that possess a TCS with shared homology. IMPORTANCE Increasing antibiotic resistance in bacteria, particularly Gram-negative bacilli, has significantly affected the ability of physicians to treat infections, with resultant increased morbidity, mortality, and health care costs. In fact, some strains of bacteria are resistant to all available antibiotics, such as Acinetobacter baumannii, which is the focus of this report. Therefore, the development of new antibiotics active against these resistant strains is urgently needed. In this study, BfmR is further validated as an intriguing target for a novel class of antibiotics. Successful inactivation of BfmR would confer the multiple benefits of a decreased ability of A. baumannii to survive in human body fluids, increased sensitivity to complement-mediated bactericidal activity and, importantly, increased sensitivity to other antibiotics. Structural studies support the potential for this “druggable” target, as they identify the potential for small-molecule binding at functionally relevant sites. Next-phase high-throughput screening studies utilizing BfmR are warranted.Thomas A. RussoAkshay ManoharJanet M. BeananRuth OlsonUlrike MacDonaldJessica GrahamTimothy C. UmlandAmerican Society for MicrobiologyarticleAcinetobacter baumanniiGram-negative bacilliantibiotic targetbacterial drug targetdrug discoveryessential genesMicrobiologyQR1-502ENmSphere, Vol 1, Iss 3 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Acinetobacter baumannii Gram-negative bacilli antibiotic target bacterial drug target drug discovery essential genes Microbiology QR1-502
spellingShingle	Acinetobacter baumannii Gram-negative bacilli antibiotic target bacterial drug target drug discovery essential genes Microbiology QR1-502 Thomas A. Russo Akshay Manohar Janet M. Beanan Ruth Olson Ulrike MacDonald Jessica Graham Timothy C. Umland The Response Regulator BfmR Is a Potential Drug Target for <named-content content-type="genus-species">Acinetobacter baumannii</named-content>
description	ABSTRACT Identification and validation is the first phase of target-based antimicrobial development. BfmR (RstA), a response regulator in a two-component signal transduction system (TCS) in Acinetobacter baumannii, is an intriguing potential antimicrobial target. A unique characteristic of BfmR is that its inhibition would have the dual benefit of significantly decreasing in vivo survival and increasing sensitivity to selected antimicrobials. Studies on the clinically relevant strain AB307-0294 have shown BfmR to be essential in vivo. Here, we demonstrate that this phenotype in strains AB307-0294 and AB908 is mediated, in part, by enabling growth in human ascites fluid and serum. Further, BfmR conferred resistance to complement-mediated bactericidal activity that was independent of capsular polysaccharide. Importantly, BfmR also increased resistance to the clinically important antimicrobials meropenem and colistin. BfmR was highly conserved among A. baumannii strains. The crystal structure of the receiver domain of BfmR was determined, lending insight into putative ligand binding sites. This enabled an in silico ligand binding analysis and a blind docking strategy to assess use as a potential druggable target. Predicted binding hot spots exist at the homodimer interface and the phosphorylation site. These data support pursuing the next step in the development process, which includes determining the degree of inhibition needed to impact growth/survival and the development a BfmR activity assay amenable to high-throughput screening for the identification of inhibitors. Such agents would represent a new class of antimicrobials active against A. baumannii which could be active against other Gram-negative bacilli that possess a TCS with shared homology. IMPORTANCE Increasing antibiotic resistance in bacteria, particularly Gram-negative bacilli, has significantly affected the ability of physicians to treat infections, with resultant increased morbidity, mortality, and health care costs. In fact, some strains of bacteria are resistant to all available antibiotics, such as Acinetobacter baumannii, which is the focus of this report. Therefore, the development of new antibiotics active against these resistant strains is urgently needed. In this study, BfmR is further validated as an intriguing target for a novel class of antibiotics. Successful inactivation of BfmR would confer the multiple benefits of a decreased ability of A. baumannii to survive in human body fluids, increased sensitivity to complement-mediated bactericidal activity and, importantly, increased sensitivity to other antibiotics. Structural studies support the potential for this “druggable” target, as they identify the potential for small-molecule binding at functionally relevant sites. Next-phase high-throughput screening studies utilizing BfmR are warranted.
format	article
author	Thomas A. Russo Akshay Manohar Janet M. Beanan Ruth Olson Ulrike MacDonald Jessica Graham Timothy C. Umland
author_facet	Thomas A. Russo Akshay Manohar Janet M. Beanan Ruth Olson Ulrike MacDonald Jessica Graham Timothy C. Umland
author_sort	Thomas A. Russo
title	The Response Regulator BfmR Is a Potential Drug Target for <named-content content-type="genus-species">Acinetobacter baumannii</named-content>
title_short	The Response Regulator BfmR Is a Potential Drug Target for <named-content content-type="genus-species">Acinetobacter baumannii</named-content>
title_full	The Response Regulator BfmR Is a Potential Drug Target for <named-content content-type="genus-species">Acinetobacter baumannii</named-content>
title_fullStr	The Response Regulator BfmR Is a Potential Drug Target for <named-content content-type="genus-species">Acinetobacter baumannii</named-content>
title_full_unstemmed	The Response Regulator BfmR Is a Potential Drug Target for <named-content content-type="genus-species">Acinetobacter baumannii</named-content>
title_sort	response regulator bfmr is a potential drug target for <named-content content-type="genus-species">acinetobacter baumannii</named-content>
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/0bbb530e852f461ea2681f39154ed515
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The Response Regulator BfmR Is a Potential Drug Target for <named-content content-type="genus-species">Acinetobacter baumannii</named-content>

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