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In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin

The mechanisms underlying bacterial tolerance to antibiotics are unclear. A possible adaptation strategy was explored by exposure of drug-naive methicillin-susceptible Staphylococcus aureus strain FDA209P to vancomycin in vitro. Strains surviving vancomycin treatment (vancomycin survivor strains), w...

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Autores principales: Singh, Madhuri, Matsuo, Miki, Sasaki, Takashi, Morimoto, Yuh, Hishinuma, Tomomi, Hiramatsu, Keiichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278750/
https://www.ncbi.nlm.nih.gov/pubmed/27855063
http://dx.doi.org/10.1128/AAC.01154-16
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author Singh, Madhuri
Matsuo, Miki
Sasaki, Takashi
Morimoto, Yuh
Hishinuma, Tomomi
Hiramatsu, Keiichi
author_facet Singh, Madhuri
Matsuo, Miki
Sasaki, Takashi
Morimoto, Yuh
Hishinuma, Tomomi
Hiramatsu, Keiichi
author_sort Singh, Madhuri
collection PubMed
description The mechanisms underlying bacterial tolerance to antibiotics are unclear. A possible adaptation strategy was explored by exposure of drug-naive methicillin-susceptible Staphylococcus aureus strain FDA209P to vancomycin in vitro. Strains surviving vancomycin treatment (vancomycin survivor strains), which appeared after 96 h of exposure, were slow-growing derivatives of the parent strain. Although the vancomycin MICs for the survivor strains were within the susceptible range, the cytokilling effects of vancomycin at 20-fold the MIC were significantly lower for the survivor strains than for the parent strain. Whole-genome sequencing demonstrated that ileS, encoding isoleucyl-tRNA synthetase (IleRS), was mutated in two of the three vancomycin survivor strains. The IleRS Y723H mutation is located close to the isoleucyl-tRNA contact site and potentially affects the affinity of IleRS binding to isoleucyl-tRNA, thereby inhibiting protein synthesis and leading to vancomycin tolerance. Introduction of the mutation encoding IleRS Y723H into FDA209P by allelic replacement successfully transferred the vancomycin tolerance phenotype. We have identified mutation of ileS to be one of the bona fide genetic events leading to the acquisition of vancomycin tolerance in S. aureus, potentially acting via inhibition of the function of IleRS.
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spelling pubmed-52787502017-02-06 In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin Singh, Madhuri Matsuo, Miki Sasaki, Takashi Morimoto, Yuh Hishinuma, Tomomi Hiramatsu, Keiichi Antimicrob Agents Chemother Mechanisms of Resistance The mechanisms underlying bacterial tolerance to antibiotics are unclear. A possible adaptation strategy was explored by exposure of drug-naive methicillin-susceptible Staphylococcus aureus strain FDA209P to vancomycin in vitro. Strains surviving vancomycin treatment (vancomycin survivor strains), which appeared after 96 h of exposure, were slow-growing derivatives of the parent strain. Although the vancomycin MICs for the survivor strains were within the susceptible range, the cytokilling effects of vancomycin at 20-fold the MIC were significantly lower for the survivor strains than for the parent strain. Whole-genome sequencing demonstrated that ileS, encoding isoleucyl-tRNA synthetase (IleRS), was mutated in two of the three vancomycin survivor strains. The IleRS Y723H mutation is located close to the isoleucyl-tRNA contact site and potentially affects the affinity of IleRS binding to isoleucyl-tRNA, thereby inhibiting protein synthesis and leading to vancomycin tolerance. Introduction of the mutation encoding IleRS Y723H into FDA209P by allelic replacement successfully transferred the vancomycin tolerance phenotype. We have identified mutation of ileS to be one of the bona fide genetic events leading to the acquisition of vancomycin tolerance in S. aureus, potentially acting via inhibition of the function of IleRS. American Society for Microbiology 2017-01-24 /pmc/articles/PMC5278750/ /pubmed/27855063 http://dx.doi.org/10.1128/AAC.01154-16 Text en Copyright © 2017 Singh et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Mechanisms of Resistance
Singh, Madhuri
Matsuo, Miki
Sasaki, Takashi
Morimoto, Yuh
Hishinuma, Tomomi
Hiramatsu, Keiichi
In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin
title In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin
title_full In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin
title_fullStr In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin
title_full_unstemmed In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin
title_short In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin
title_sort in vitro tolerance of drug-naive staphylococcus aureus strain fda209p to vancomycin
topic Mechanisms of Resistance
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278750/
https://www.ncbi.nlm.nih.gov/pubmed/27855063
http://dx.doi.org/10.1128/AAC.01154-16
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