Daptomycin membrane activity is modulated by the localized interplay between calcium ions and phospholipids in monolayers and bilayers containing a lysyl-phosphatidylglycerol analogue

ions to a level sufficient to displace 3adLPG from ion pairs with PG, and thus binds to its target PG. In bilayers with mixed chain lipids, daptomycin leads to pronounced membrane perturbations and enhanced permeability. Sequestering all of the available PG into PG/3adLPG ion pairs, therefore, would represent a putative daptomycin non-susceptible membrane. Daptomycin binding and the extent of subsequent lipid structural changes are reduced in these membranes. This implies that in bacteria, native LPG biosynthesis would need to ensure either an equivalence or an excess in relation to membrane PG content, in order for this mechanism alone to significantly contribute to daptomycin resistance.