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Stenotrophomonas maltophilia PhoP, a Two-Component Response Regulator, Involved in Antimicrobial Susceptibilities

Stenotrophomonas maltophilia, a gram-negative bacterium, has increasingly emerged as an important nosocomial pathogen. It is well-known for resistance to a variety of antimicrobial agents including cationic antimicrobial polypeptides (CAPs). Resistance to polymyxin B, a kind of CAPs, is known to be...

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Autores principales: Liu, Ming-Che, Tsai, Yi-Lin, Huang, Yi-Wei, Chen, Hsing-Yu, Hsueh, Po-Ren, Lai, Szu-Yu, Chen, Li-Chia, Chou, Yi-Hwa, Lin, Wen-Yuan, Liaw, Shwu-Jen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861329/
https://www.ncbi.nlm.nih.gov/pubmed/27159404
http://dx.doi.org/10.1371/journal.pone.0153753
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author Liu, Ming-Che
Tsai, Yi-Lin
Huang, Yi-Wei
Chen, Hsing-Yu
Hsueh, Po-Ren
Lai, Szu-Yu
Chen, Li-Chia
Chou, Yi-Hwa
Lin, Wen-Yuan
Liaw, Shwu-Jen
author_facet Liu, Ming-Che
Tsai, Yi-Lin
Huang, Yi-Wei
Chen, Hsing-Yu
Hsueh, Po-Ren
Lai, Szu-Yu
Chen, Li-Chia
Chou, Yi-Hwa
Lin, Wen-Yuan
Liaw, Shwu-Jen
author_sort Liu, Ming-Che
collection PubMed
description Stenotrophomonas maltophilia, a gram-negative bacterium, has increasingly emerged as an important nosocomial pathogen. It is well-known for resistance to a variety of antimicrobial agents including cationic antimicrobial polypeptides (CAPs). Resistance to polymyxin B, a kind of CAPs, is known to be controlled by the two-component system PhoPQ. To unravel the role of PhoPQ in polymyxin B resistance of S. maltophilia, a phoP mutant was constructed. We found MICs of polymyxin B, chloramphenicol, ampicillin, gentamicin, kanamycin, streptomycin and spectinomycin decreased 2–64 fold in the phoP mutant. Complementation of the phoP mutant by the wild-type phoP gene restored all of the MICs to the wild type levels. Expression of PhoP was shown to be autoregulated and responsive to Mg(2+) levels. The polymyxin B and gentamicin killing tests indicated that pretreatment of low Mg(2+) can protect the wild-type S. maltophilia from killing but not phoP mutant. Interestingly, we found phoP mutant had a decrease in expression of SmeZ, an efflux transporter protein for aminoglycosides in S. maltophilia. Moreover, phoP mutant showed increased permeability in the cell membrane relative to the wild-type. In summary, we demonstrated the two-component regulator PhoP of S. maltophilia is involved in antimicrobial susceptibilities and low Mg(2+) serves as a signal for triggering the pathway. Both the alteration in membrane permeability and downregulation of SmeZ efflux transporter in the phoP mutant contributed to the increased drug susceptibilities of S. maltophilia, in particular for aminoglycosides. This is the first report to describe the role of the Mg(2+)-sensing PhoP signaling pathway of S. maltophilia in regulation of the SmeZ efflux transporter and in antimicrobial susceptibilities. This study suggests PhoPQ TCS may serve as a target for development of antimicrobial agents against multidrug-resistant S. maltophilia.
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spelling pubmed-48613292016-05-13 Stenotrophomonas maltophilia PhoP, a Two-Component Response Regulator, Involved in Antimicrobial Susceptibilities Liu, Ming-Che Tsai, Yi-Lin Huang, Yi-Wei Chen, Hsing-Yu Hsueh, Po-Ren Lai, Szu-Yu Chen, Li-Chia Chou, Yi-Hwa Lin, Wen-Yuan Liaw, Shwu-Jen PLoS One Research Article Stenotrophomonas maltophilia, a gram-negative bacterium, has increasingly emerged as an important nosocomial pathogen. It is well-known for resistance to a variety of antimicrobial agents including cationic antimicrobial polypeptides (CAPs). Resistance to polymyxin B, a kind of CAPs, is known to be controlled by the two-component system PhoPQ. To unravel the role of PhoPQ in polymyxin B resistance of S. maltophilia, a phoP mutant was constructed. We found MICs of polymyxin B, chloramphenicol, ampicillin, gentamicin, kanamycin, streptomycin and spectinomycin decreased 2–64 fold in the phoP mutant. Complementation of the phoP mutant by the wild-type phoP gene restored all of the MICs to the wild type levels. Expression of PhoP was shown to be autoregulated and responsive to Mg(2+) levels. The polymyxin B and gentamicin killing tests indicated that pretreatment of low Mg(2+) can protect the wild-type S. maltophilia from killing but not phoP mutant. Interestingly, we found phoP mutant had a decrease in expression of SmeZ, an efflux transporter protein for aminoglycosides in S. maltophilia. Moreover, phoP mutant showed increased permeability in the cell membrane relative to the wild-type. In summary, we demonstrated the two-component regulator PhoP of S. maltophilia is involved in antimicrobial susceptibilities and low Mg(2+) serves as a signal for triggering the pathway. Both the alteration in membrane permeability and downregulation of SmeZ efflux transporter in the phoP mutant contributed to the increased drug susceptibilities of S. maltophilia, in particular for aminoglycosides. This is the first report to describe the role of the Mg(2+)-sensing PhoP signaling pathway of S. maltophilia in regulation of the SmeZ efflux transporter and in antimicrobial susceptibilities. This study suggests PhoPQ TCS may serve as a target for development of antimicrobial agents against multidrug-resistant S. maltophilia. Public Library of Science 2016-05-09 /pmc/articles/PMC4861329/ /pubmed/27159404 http://dx.doi.org/10.1371/journal.pone.0153753 Text en © 2016 Liu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Liu, Ming-Che
Tsai, Yi-Lin
Huang, Yi-Wei
Chen, Hsing-Yu
Hsueh, Po-Ren
Lai, Szu-Yu
Chen, Li-Chia
Chou, Yi-Hwa
Lin, Wen-Yuan
Liaw, Shwu-Jen
Stenotrophomonas maltophilia PhoP, a Two-Component Response Regulator, Involved in Antimicrobial Susceptibilities
title Stenotrophomonas maltophilia PhoP, a Two-Component Response Regulator, Involved in Antimicrobial Susceptibilities
title_full Stenotrophomonas maltophilia PhoP, a Two-Component Response Regulator, Involved in Antimicrobial Susceptibilities
title_fullStr Stenotrophomonas maltophilia PhoP, a Two-Component Response Regulator, Involved in Antimicrobial Susceptibilities
title_full_unstemmed Stenotrophomonas maltophilia PhoP, a Two-Component Response Regulator, Involved in Antimicrobial Susceptibilities
title_short Stenotrophomonas maltophilia PhoP, a Two-Component Response Regulator, Involved in Antimicrobial Susceptibilities
title_sort stenotrophomonas maltophilia phop, a two-component response regulator, involved in antimicrobial susceptibilities
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861329/
https://www.ncbi.nlm.nih.gov/pubmed/27159404
http://dx.doi.org/10.1371/journal.pone.0153753
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