Analogues of A Cyclic Antimicrobial Peptide with A Flexible Linker Show Promising Activity against Pseudomonas Aeruginosa and Staphylococcus Aureus .

The emergence of multi-drug resistant bacteria is becoming a major health concern. New strategies to combat especially Gram-negative pathogens are urgently needed. Antimicrobial peptides (AMPs) found in all multicellular organisms act as a first line of defense in immunity. In recent years, AMPs have attracted increasing attention as potential antibiotics. Naturally occurring antimicrobial cyclic lipopeptides include colistin and daptomycin, both of which contain a flexible linker. We previously reported a cyclic AMP BSI-9 cyclo(Lys-Nal-Lys-Lys-Bip-O(2)Oc-Nal-Lys-Asn) containing a flexible linker, with a broad spectrum of activity against bacterial strains and low hemolytic activity. In this study, improvement of the antimicrobial activity of BSI-9, against the European Committee on Antimicrobial Susceptibility Testing (EUCAST) strains ofS. aureus,E. coli,A. baumannii, andP. aeruginosawas examined. This led to synthesis of eighteen peptide analogues of BSI-9, produced in four individual stages, with a different focus in each stage; cyclization point, hydrophobicity, cationic side-chain length, and combinations of the last two. Specifically the modified compound 11, exhibited improved activity againstStaphylococcus aureusandPseudomonas aeruginosawith MIC of 4 mu g/mL and 8 mu g/mL, respectively, compared to the original BSI-9, which had an MIC of 16-32 mu g/mL.