Rajamani Lakshminarayanan
Singapore Eye Research Institute, Singapore
Title: Rational Design of Cell-selective Antimicrobial Peptides
Biography
Biography: Rajamani Lakshminarayanan
Abstract
The evolution of antibiotic-resistant pathogens pose significant threat to human health and healthcare systems and account for considerable economic burden world-wide. In particular, the Gram-negative bacteria adapted sophisticated machineries that can overcome all the available pathways targeted by current antibiotics. Agents that target cytoplasmic membranes of prokaryotes are attractive alternatives for combating antimicrobial resistance owing. Cationic antimicrobial host defense peptides have been shown to elicit rapid bactericidal action by targeting cytoplasmic membrane of the bacteria, but their cytotoxicity for mammalian cells limited their therapeutic potential. Our preliminary investigations that the cationic polymer ε-polylysine has superior cellselectivity
than isomeric α-polylysine. Based on this preliminary data, we replaced α-lysine residues in prolific pore forming peptide, melittin from bee venom, with ε-lysine residues and determined their cell selectivity. Melittin elicited toxic effect on both microbial as well as mammalian cells confirming its poor cell selectivity. However, substitution of N-terminal α-lysine with ε-lysine residues increased the cell selectivity while C-terminal substitution did not alter the properties. Multiple substitution of ε-lysyl residues enhanced the cell selectivity significantly. Two such peptides displayed excellent antimicrobial activities against MRSA, vancomycinresistant enterococci, antibiotic-resistant P. aeruginosa, carbapenem-resistant enterobacteriacae and azole-resistant Candida spp strains. The modified melittin peptides display rapid bactericial properties and slightly weaker pore-forming properties than melittin
while non-cytotoxic for mammalian cells. We further confirmed the enhanced cell selectivity upon ï¥-lysylation in mastoparan B, the antimicrobial peptide present in harnet’s venom. Together, these results establish the rational modification of multifunctional hostdefense peptides by ï¥-lysylation with improved cell selectivity.