Compensatory mutations in agrC partly restore fitness in vitro to peptide deformylase inhibitor-resistant Staphylococcus aureus

The Journal of Antimicrobial Chemotherapy
Anna ZorzetDan I Andersson

Abstract

To determine how the fitness cost of deformylase inhibitor resistance conferred by fmt mutations can be genetically compensated. Resistant mutants were isolated and characterized with regard to their growth rates in vitro and in neutropenic mice, MIC and DNA sequence. Faster-growing compensated mutants were isolated by serial passage in culture medium, and for a subset of the resistant and compensated mutants whole-genome sequencing was performed. Staphylococcus aureus mutants resistant to the peptide deformylase inhibitor actinonin had mutations in the fmt gene that conferred high-level actinonin resistance and reduced bacterial growth rate. Compensated mutants that remained fully resistant to actinonin and showed increased growth rates appeared within 30-60 generations of growth. Whole-genome sequencing and localized DNA sequencing of mutated candidate genes showed that alterations in the gene agrC were present in the majority of compensated strains. Resistant and compensated mutants grew at similar rates as the wild-type in a mouse thigh infection model. Resistance to deformylase inhibitors due to fmt mutations reduces bacterial growth rates, but these costs can be reduced by mutations in the agrC gene. Mutants defective in ...Continue Reading

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Citations

Apr 11, 2013·Antimicrobial Agents and Chemotherapy·Thomas LewandowskiMagdalena Zalacain
Sep 27, 2014·Evolution; International Journal of Organic Evolution·Henri DarmencyChristophe Délye
Apr 11, 2015·Evolutionary Applications·Tom Vogwill, R Craig MacLean
Dec 17, 2016·Microbiology·Yanfei CaiJohn D Helmann
Oct 21, 2016·Scientific Reports·Sonia FieulaineCarmela Giglione
Nov 20, 2016·Annals of the New York Academy of Sciences·José L MartínezFernando Baquero

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