title: Staphylococcus aureus metabolic adaptations during the transition from a daptomycin susceptibility phenotype to a daptomycin nonsusceptibility phenotype.
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.
authors.affiliation: School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: Rosmarie
authors.initials: R
authors.lastname: Gaupp
authors.affiliation: Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: Shulei
authors.initials: S
authors.lastname: Lei
authors.affiliation: School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Reed
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Saarland, Homburg/Saar, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Peisker
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Boyle-Vavra
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Saarland, Homburg/Saar, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bischoff
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Saarland, Homburg/Saar, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Daum
authors.affiliation: Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA gsomerville3@unl.edu rpowers3@unl.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Powers
authors.affiliation: School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA gsomerville3@unl.edu rpowers3@unl.edu.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Somerville
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002473:Cell Wall / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects; D017576:Daptomycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010457:Peptidoglycan / Q000737:chemistry / Q000378:metabolism; D010641:Phenotype; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013682:Teichoic Acids / Q000378:metabolism; D020713:Vancomycin Resistance / Q000235:genetics
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D010457:Peptidoglycan; D011687:Purines; D011743:Pyrimidines; D013682:Teichoic Acids; D000154:Aconitate Hydratase; D017576:Daptomycin