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Antimicrob Agents Chemother. 2015 Sep;59(9):5366-76. doi: 10.1128/AAC.00643-15. Epub 2015 Jun 22.

A novel point mutation promotes growth phase-dependent daptomycin tolerance in Staphylococcus aureus.

Author information

1
Department of Microbial Genetics, Faculty of Science, Interfaculty Institute of Microbiology and Infection Medicine Tübingen, University of Tübingen, Tübingen, Germany.
2
Department of Archaeological Sciences, University of Tübingen, Tübingen, Germany Center for Bioinformatics, University of Tübingen, Tübingen, Germany.
3
Department of Microbiology, University of Würzburg, Würzburg, Germany.
4
Center for Bioinformatics, University of Tübingen, Tübingen, Germany.
5
Department of Microbial Genetics, Faculty of Science, Interfaculty Institute of Microbiology and Infection Medicine Tübingen, University of Tübingen, Tübingen, Germany ralph.bertram@pmu.ac.at.

Abstract

Recalcitrance of genetically susceptible bacteria to antibiotic killing is a hallmark of bacterial drug tolerance. This phenomenon is prevalent in biofilms, persisters, and also planktonic cells and is associated with chronic or relapsing infections with pathogens such as Staphylococcus aureus. Here we report the in vitro evolution of an S. aureus strain that exhibits a high degree of nonsusceptibility to daptomycin as a result of cyclic challenges with bactericidal concentrations of the drug. This phenotype was attributed to stationary growth phase-dependent drug tolerance and was clearly distinguished from resistance. The underlying genetic basis was revealed to be an adaptive point mutation in the putative inorganic phosphate (Pi) transporter gene pitA. Drug tolerance caused by this allele, termed pitA6, was abrogated when the upstream gene pitR was inactivated. Enhanced tolerance toward daptomycin, as well as the acyldepsipeptide antibiotic ADEP4 and various combinations of other drugs, was accompanied by elevated intracellular concentrations of Pi and polyphosphate, which may reversibly interfere with critical cellular functions. The evolved strain displayed increased rates of survival within human endothelial cells, demonstrating the correlation of intracellular persistence and drug tolerance. These findings will be useful for further investigations of S. aureus drug tolerance, toward the development of additional antipersister compounds and strategies.

PMID:
26100694
PMCID:
PMC4538524
DOI:
10.1128/AAC.00643-15
[Indexed for MEDLINE]
Free PMC Article

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