Side Chain Hydrophobicity Modulates Therapeutic Activity and Membrane Selectivity of Antimicrobial Peptide Mastoparan-X

摘要: The discovery of new anti-infective compounds is stagnating and multi-resistant bacteria continue to emerge, threatening end the “antibiotic era”. Antimicrobial peptides (AMPs) lipo-peptides such as daptomycin offer themselves a potential class antibiotics; however, further optimization needed if AMPs are find broad use antibiotics. In present work, eight analogues mastoparan-X (MPX) were investigated, having side chain modifications in position 1, 8 14 modulate peptide hydrophobicity. self-association properties characterized, peptide-membrane interactions model membranes compared with bactericidal haemolytic properties. Alanine substitution at 1 resulted higher target selectivity (red blood cells versus bacteria), but also decreased potency. For these analogues, gain correlated biophysical parameters showing an increased effective charge reduction partitioning coefficient for membrane insertion. Introduction unnatural amino acid, octyl by acid substitution, positions potency expense radically reduced selectivity. Overall, optimized or was achieved changes hydrophobicity MPX. However, enhanced vice versa all cases.