Lysyl-phosphatidylglycerol attenuates membrane perturbation rather than surface association of the cationic antimicrobial peptide 6W-RP-1 in a model membrane system: implications for daptomycin resistance.

The presence of the cationic phospholipid lysyl-phosphatidylglycerol (lysyl-PG) in staphylococcal cytoplasmic membranes has been linked to increased resistance to cationic compounds, including antibiotics such as daptomycin as well as host defense antimicrobial peptides. We investigated the effects of lysyl-PG on binding of 6W-RP-1, a synthetic antimicrobial peptide, to lipid vesicles and on peptide-induced membrane permeabilization. Unexpectedly, physiological lysyl-PG concentrations only minimally reduced membrane binding of 6W-RP-1. In contrast, 6W-RP-1-induced dye leakage was severely inhibited by lysyl-PG, suggesting that lysyl-PG primarily impacts membrane defect formation.