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.