Low pH Enhances the Action of Maximin H5 against Staphylococcus aureus and Helps Mediate Lysylated Phosphatidylglycerol-Induced Resistance

Maximin H5 (MH5) is an amphibian antimicrobial peptide specifically targeting Staphylococcus aureus. At pH 6, the peptide showed an improved ability to penetrate (Delta Pi = 6.2 mN m(-1)) and lyse (lysis = 48%) Staphylococcus aureus membrane mimics, which incorporated physiological levels of lysylated phosphatidylglycerol (Lys-PG, 60%), compared to that at pH 7 (Delta Pi = 5.6 mN m(-1) and lysis = 40% at pH 7) where levels of Lys-PG are lower (40%). The peptide therefore appears to have optimal function at pH levels known to be optimal for the organism's growth. MH5 killed S. aureus (minimum inhibitory concentration of 90 mu M) via membranolytic mechanisms that involved the stabilization of alpha-helical structure (approximately 45-50%) and showed similarities to the Carpet mechanism based on its ability to increase the rigidity (C-s(-1) = 109.94 mN m(-1)) and thermodynamic stability (Delta G(mix) = -3.0) of physiologically relevant S. aureus membrane mimics at pH 6. On the basis of theoretical analysis, this mechanism might involve the use of a tilted peptide structure, and efficacy was noted to vary inversely with the Lys-PG content of S. aureus membrane mimics for each pH studied (R-2 similar to 0.97), which led to the suggestion that under biologically relevant conditions, low pH helps mediate Lys-PG-induced resistance in S. aureus to MHS antibacterial action. The peptide showed a lack of hemolytic activity (<2% hemolysis) and merits further investigation as a potential template for development as an antistaphylococcal agent in medically and biotechnically relevant areas.