Cardiolipin induces strong inhibition of the short antimicrobial peptide Atra-1, but only weak inhibition of LL-37 in saturated model membranes.

Abstract

Cardiolipin (CL) is an anionic tetra-acyl chained glycerophospholipid that increases lipid packing levels and induces intrinsic negative curvature in membranes. Cardiolipin is one of the main components in Staphylococcus aureus membranes, where increased levels of this lipid are induced at the expense of diacyl phosphatidylglycerol in response to stress. We investigate cardiolipin as an inhibitor of the lytic activity of the cationic antimicrobial peptides Atra-1 and LL-37 in model systems with varying phosphatidylglycerol/cardiolipin ratios. One of the characteristic difference between these two antimicrobial peptides is their length. While Atra-1 is a short peptides with only 11 residues, LL-37 is 37 residues in length. We observe that the presence of cardiolipin increases the leakage-inducing concentration of Atra-1 by several orders of magnitude, while only doubling that for LL-37. We find that cardiolipin does not affect peptide binding to phosphatidylglycerol/cardiolipin liposomes significantly for either peptide, measured by shifts in Laurdan GP, so it is likely that CL affects the insertion into the membrane. We measure by FTIR the thermotropic behavior of the model systems in the presence of the peptides. In the absence of CL, both peptides induce shifts in the gel to liquid-crystalline phase transition temperature, but in the presence of CL this shift was strongly reduced in the case of Atra-1. These results suggest that CL can inhibit cAMP activity drastically depending on the antimicrobial peptide structure.