Rational Substitution of ε-Lysine for α-Lysine Enhances the Cell and Membrane Selectivity of Pore-Forming Melittin.
Venkatesh MayandiQingxiao XiGoh LengSiew Kwan KohToh JieVeluchamy Amutha BarathiMobashar Hussain Urf Turabe FazilMadhavi Latha Somaraju ChalasaniJayasudha VaradarajanDarren Shu Jeng TingRoger W BeuermanLai Wah ChanRupesh AgrawalBarkham SebastianLei ZhouNavin Kumar VermaLakshminarayanan RajamaniPublished in: Journal of medicinal chemistry (2020)
Here, we present a rational approach that enhances the membrane selectivity of a prolific pore-forming peptide, melittin, based on experimental observations that the cationic polymer, ε-polylysine, disrupts bacterial membranes with greater affinity over mammalian cells when compared to poly-l-lysine and poly-d-lysine. We systematically replaced three α-lysine residues in melittin with ε-lysine residues and identified key residues that are important for cytotoxicity. We then assessed the antimicrobial properties of the modified peptides which carry two or three ε-lysyl residues. Two modified melittin peptides displayed rapid bactericidal properties against antibiotic-resistant strains, low innate resistance development by pathogenic bacteria, remained nonimmunogenic for T lymphocytes, and increased bioavailability in tear fluids. In proof-of-concept in vivo experiments, one of the peptides was noncytotoxic for ocular surfaces and had comparable antimicrobial efficacy to that of fluoroquinolone antibiotics. The results uncover a simple and potential strategy that can enhance the membrane selectivity of cytolytic peptides by ε-lysylation.