Staphylococcus aureus Metabolic Adaptations during the Transition from a Daptomycin Susceptibility Phenotype to a Daptomycin Nonsusceptibility Phenotype

Authors

Rosmarie Gaupp, University of Nebraska-Lincoln
Shulei Lei, University of Nebraska-Lincoln
Joseph M. Reed, University of Nebraska-Lincoln
Henrik Peisker, University of Saarland
Susan Boyle- Vavra, University of Chicago
Arnold S. Bayer, UCLA Medical Center
Markus Bischoff, University of SaarlandFollow
Mathias Herrmann, University of Saarland
Robert S. Daum, University of Chicago
R. D. Powell, Northern Illinois UniversityFollow
Greg A. Somerville, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

2015

Citation

Antimicrob Agents Chemother 59:4226–4238. doi:10.1128/AAC.00160-15.

Comments

© 2015, American Society for Microbiology. All Rights Reserved

Abstract

Staphylococcus aureus is a major cause of nosocomial and community-acquired infections. The success of S. aureus as a pathogen is due in part to its many virulence determinants and resistance to antimicrobials. In particular, methicillin-resistant S. aureus has emerged as a major cause of infections and led to increased use of the antibiotics vancomycin and daptomycin, which has increased the isolation of vancomycin-intermediate S. aureus and daptomycin-nonsusceptible S. aureus strains. The most common mechanism by which S. aureus acquires intermediate resistance to antibiotics is by adapting its physiology and metabolism to permit growth in the presence of these antibiotics, a process known as adaptive resistance. To better understand the physiological and metabolic changes associated with adaptive resistance, six daptomycin-susceptible and -nonsusceptible isogenic strain pairs were examined for changes in growth, competitive fitness, and metabolic alterations. Interestingly, daptomycin nonsusceptibility coincides with a slightly delayed transition to the postexponential growth phase and alterations in metabolism. Specifically, daptomycin-nonsusceptible strains have decreased tricarboxylic acid cycle activity, which correlates with increased synthesis of pyrimidines and purines and increased carbon flow to pathways associated with wall teichoic acid and peptidoglycan biosynthesis. Importantly, these data provided an opportunity to alter the daptomycin nonsusceptibility phenotype by manipulating bacterial metabolism, a first step in developing compounds that target metabolic pathways that can be used in combination with daptomycin to reduce treatment failures.