Daptomycin In Vitro Activity against Methicillin-Resistant Staphylococcus aureus Is Enhanced by D-Cycloserine in a Mechanism Associated with a Decrease in Cell Surface Charge

The killing activity of daptomycin against an isogenic pair of daptomycin-susceptible and daptomycin-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) strains was enhanced by the addition of certain cell wall agents at 1MIC. However, when high inocula of the DNS strain were used, no significant killing was observed in our experiments. Cytochrome c binding assays revealed D-cycloserine as the only agent associated with a reduction in the cell surface charge for both strains at the concentrations used. The mechanisms of resistance to daptomycin (DAP) in Staphy-lococcus aureus have been related to cell membrane alterations such as cell wall thickening, modifications in membrane lipid composition, altered drug binding, and changes in the surface charge (1). Almost all synthesis of (the positively charged) D-alanine in S. aureus is controlled by alanine racemase (2, 3). D-Cycloserine (DCS) is a D-alanine analog used as a second-line treatment for mycobacterial infections. It prevents peptidoglycan synthesis in the bacterial cell wall by competitive inhibition of both the alanine racemase and D-alanine ligase enzymes (4, 5)