Metabolic interventions for the prevention and treatment of daptomycin non-susceptibility in Staphylococcus aureus.

Background: A major developing problem in the treatment of Staphylococcus aureus infections is the emergence of resistance during treatment with daptomycin. Previous metabolomic analyses of isogenic S. aureus strains prior to and after evolution into a daptomycin non-susceptible (Dap(NS)) state provided important metabolic information about this transition (e.g. perturbations of the tricarboxylic acid cycle). Objectives: To assess the significance of these metabolic changes, in vitro susceptibility to daptomycin was determined in daptomycin-susceptible (Dap(S)) and Dap(NS) S. aureus strains cultivated with metabolic inhibitors targeting these changes. Methods: Only inhibitors that are approved for use in humans were chosen (i.e. fosfomycin, valproate, trimetazidine and 6-mercaptopurine) to assess the importance of metabolic pathways for daptomycin non-susceptibility. The ability of these inhibitors to forestall the emergence of DapNS strains was also assessed. Results: The combination of daptomycin and fosfomycin synergistically killed both Dap(S) and Dap(NS) strains in vitro and enhanced the in vivo outcome against a Dap(NS) strain in experimental endocarditis. Interestingly, fosfomycin acts on the peptidoglycan biosynthetic enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA); however, it also had a significant effect on the enzymatic activity of enolase, an essential enzyme in S. aureus. While fosfomycin acted synergistically with daptomycin, it failed to prevent the in vitro evolution of daptomycin non-susceptibility. In contrast, trimetazidine, an anti-angina drug that stimulates glucose oxidation, abolished the ability of Dap(S) S. aureus strains to transition to a Dap(NS) state. Conclusions: These data reveal that metabolic adaptations associated with Dap(NS) strains can be targeted to prevent the emergence of and/or reverse pre-existing resistance to daptomycin.