Metabolic mitigation of staphylococcus aureus vancomycin intermediate-level susceptibility
JournalAntimicrobial Agents and Chemotherapy
PublisherAmerican Society for Microbiology
MetadataShow full item record
AbstractStaphylococcus aureus is a major human pathogen whose infections are increasingly difficult to treat due to increased antibiotic resistance, including resistance to vancomycin. Vancomycin-intermediate S. aureus (VISA) strains develop resistance to vancomycin through adaptive changes that are incompletely understood. Central to this adaptation are metabolic changes that permit growth in the presence of vancomycin. To define the metabolic changes associated with adaptive resistance to vancomycin in S. aureus, the metabolomes of a vancomycin-sensitive and VISA strain pair isolated from the same patient shortly after vancomycin therapy began and following vancomycin treatment failure were analyzed. The metabolic adaptations included increases in acetogenesis, carbon flow through the pentose phosphate pathway, wall teichoic acid and peptidoglycan precursor biosynthesis, purine biosynthesis, and decreased tricarboxylic acid (TCA) cycle activity. The significance of these metabolic pathways for vancomycin-intermediate susceptibility was determined by assessing the synergistic potential of human-use-approved inhibitors of these pathways in combination with vancomycin against VISA strains. Importantly, inhibitors of amino sugar and purine biosynthesis acted synergistically with vancomycin to kill a diverse set of VISA strains, suggesting that combinatorial therapy could augment the efficacy of vancomycin even in patients infected with VISA strains. Copyright Copyright 2017 American Society for Microbiology. All Rights Reserved.
SponsorsThis work was supported in part by funding from the Redox Biology Center (P30 GM103335, NIGMS) and the Nebraska Center for Integrated Biomolecular Communication (P20-GM113126, NIGMS), and the research was performed in facilities renovated with support from the National Institutes of Health (RR015468-01). In addition, support was provided by the Nebraska Research Initiative. We thank Susan Boyle-Vavra for helpful discussions.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85039794764&doi=10.1128%2fAAC.01608-17&partnerID=40&md5=5e93550f1b1da967f6fe3703adc1671c; http://hdl.handle.net/10713/9115