Analogues of a Cyclic Antimicrobial Peptide with a Flexible Linker Show Promising Activity against <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus</em>

• Main Authors: Thomas T. Thomsen (Author), Helen C. Mendel (Author), Wafaa Al-Mansour (Author), Alberto Oddo (Author), Anders Løbner-Olesen (Author), Paul R. Hansen (Author)
• Format: Book
• Published: MDPI AG, 2020-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics9070366; 2079-6382
• Keywords: cyclic antimicrobial peptides; antibiotics; multi-drug resistant bacteria; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 9, Iss 7, p 366 (2020)

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-O₂Oc-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 of <i>S. aureus</i>, <i>E. coli</i>, <i>A. baumannii</i>, and <i>P. aeruginosa</i> was 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 <b>11</b>, exhibited improved activity against <i>Staphylococcus aureus</i> and <i>Pseudomonas aeruginosa</i> with MIC of 4 µg/mL and 8 µg/mL, respectively, compared to the original BSI-9, which had an MIC of 16-32 µg/mL.