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Role of cpxA Mutations in the Resistance to Aminoglycosides and β-Lactams in Salmonella enterica serovar Typhimurium

Although it has been reported that deletion of the response regulator, CpxR, in the CpxRA system confers sensitivity to aminoglycosides (AGAs) and β-lactams in Salmonella enterica serovar Typhimurium, the regulatory effects of CpxA on multidrug resistance (MDR) are yet to be fully investigated in th...

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Autores principales: Jing, Wenxian, Liu, Juan, Wu, Shanshan, Li, Xuerui, Liu, Yongsheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889517/
https://www.ncbi.nlm.nih.gov/pubmed/33613478
http://dx.doi.org/10.3389/fmicb.2021.604079
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author Jing, Wenxian
Liu, Juan
Wu, Shanshan
Li, Xuerui
Liu, Yongsheng
author_facet Jing, Wenxian
Liu, Juan
Wu, Shanshan
Li, Xuerui
Liu, Yongsheng
author_sort Jing, Wenxian
collection PubMed
description Although it has been reported that deletion of the response regulator, CpxR, in the CpxRA system confers sensitivity to aminoglycosides (AGAs) and β-lactams in Salmonella enterica serovar Typhimurium, the regulatory effects of CpxA on multidrug resistance (MDR) are yet to be fully investigated in this organism. Here, to explore the role of CpxA in MDR, various cpxA mutants including a null mutant (JSΔcpxA), a site-directed mutant (JSΔcpxA(38)) and an internal in-frame deletion mutant (JSΔcpxA(92)(–)(104)) of the S. enterica serovar Typhimurium strain JS, were constructed. It was revealed that cpxA and cpxR deletion mutants have opposing roles in the regulation of resistance to AGAs and β-lactams. Amikacin and cefuroxime can activate the CpxRA system, which results in increased resistance of the wild-type compared with the cpxR deletion mutant. All the cpxA mutations significantly increased resistance to AGAs and β-lactams due to CpxRA system activation via the phosphorylation of CpxR. Moreover, AckA-Pta-dependent activation of CpxR increased the antibiotic resistance of cpxA deletion mutants. Further research revealed that the AcrAB-TolC conferred resistance to some AGAs and β-lactams but does not influence the regulation of resistance by CpxRA against these antibiotics. The detection of candidate MDR-related CpxR regulons revealed that the mRNA expression levels of spy, ycca, ppia, htpX, stm3031, and acrD were upregulated and that of ompW was downregulated in various cpxA mutants. Furthermore, the expression levels of nuoA and sdhC mRNAs were downregulated only in JSΔcpxA(92)(–)(104). These results suggested that cpxA mutations contribute to AGAs and β-lactams resistance, which is dependent on CpxR.
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spelling pubmed-78895172021-02-19 Role of cpxA Mutations in the Resistance to Aminoglycosides and β-Lactams in Salmonella enterica serovar Typhimurium Jing, Wenxian Liu, Juan Wu, Shanshan Li, Xuerui Liu, Yongsheng Front Microbiol Microbiology Although it has been reported that deletion of the response regulator, CpxR, in the CpxRA system confers sensitivity to aminoglycosides (AGAs) and β-lactams in Salmonella enterica serovar Typhimurium, the regulatory effects of CpxA on multidrug resistance (MDR) are yet to be fully investigated in this organism. Here, to explore the role of CpxA in MDR, various cpxA mutants including a null mutant (JSΔcpxA), a site-directed mutant (JSΔcpxA(38)) and an internal in-frame deletion mutant (JSΔcpxA(92)(–)(104)) of the S. enterica serovar Typhimurium strain JS, were constructed. It was revealed that cpxA and cpxR deletion mutants have opposing roles in the regulation of resistance to AGAs and β-lactams. Amikacin and cefuroxime can activate the CpxRA system, which results in increased resistance of the wild-type compared with the cpxR deletion mutant. All the cpxA mutations significantly increased resistance to AGAs and β-lactams due to CpxRA system activation via the phosphorylation of CpxR. Moreover, AckA-Pta-dependent activation of CpxR increased the antibiotic resistance of cpxA deletion mutants. Further research revealed that the AcrAB-TolC conferred resistance to some AGAs and β-lactams but does not influence the regulation of resistance by CpxRA against these antibiotics. The detection of candidate MDR-related CpxR regulons revealed that the mRNA expression levels of spy, ycca, ppia, htpX, stm3031, and acrD were upregulated and that of ompW was downregulated in various cpxA mutants. Furthermore, the expression levels of nuoA and sdhC mRNAs were downregulated only in JSΔcpxA(92)(–)(104). These results suggested that cpxA mutations contribute to AGAs and β-lactams resistance, which is dependent on CpxR. Frontiers Media S.A. 2021-02-04 /pmc/articles/PMC7889517/ /pubmed/33613478 http://dx.doi.org/10.3389/fmicb.2021.604079 Text en Copyright © 2021 Jing, Liu, Wu, Li and Liu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Jing, Wenxian
Liu, Juan
Wu, Shanshan
Li, Xuerui
Liu, Yongsheng
Role of cpxA Mutations in the Resistance to Aminoglycosides and β-Lactams in Salmonella enterica serovar Typhimurium
title Role of cpxA Mutations in the Resistance to Aminoglycosides and β-Lactams in Salmonella enterica serovar Typhimurium
title_full Role of cpxA Mutations in the Resistance to Aminoglycosides and β-Lactams in Salmonella enterica serovar Typhimurium
title_fullStr Role of cpxA Mutations in the Resistance to Aminoglycosides and β-Lactams in Salmonella enterica serovar Typhimurium
title_full_unstemmed Role of cpxA Mutations in the Resistance to Aminoglycosides and β-Lactams in Salmonella enterica serovar Typhimurium
title_short Role of cpxA Mutations in the Resistance to Aminoglycosides and β-Lactams in Salmonella enterica serovar Typhimurium
title_sort role of cpxa mutations in the resistance to aminoglycosides and β-lactams in salmonella enterica serovar typhimurium
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889517/
https://www.ncbi.nlm.nih.gov/pubmed/33613478
http://dx.doi.org/10.3389/fmicb.2021.604079
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