An amphipathic cyclic tetrapeptide scaffold containing halogenated β 2,2 -amino acids with activity against multiresistant bacteria

• Published in: Journal of peptide science 2018-10, Vol.24 (10), p.e3117
• Main Authors: Paulsen, Marianne H, Karlsen, Eskil André, Ausbacher, Dominik, Anderssen, Trude, Bayer, Annette, Ochtrop, Philipp, Hedberg, Christian, Haug, Tor, Ericson Sollid, Johanna U, Strøm, Morten B
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antimicrobial peptides; beta-amino acids; CARBA; cyclic tetrapeptides; Drug Design; Drug Resistance, Multiple, Bacterial - drug effects; ESBL; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Halogenation; Molecular Structure; MRSA; multiresistant bacteria; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; peptidomimetics; SMAMPs; Structure-Activity Relationship; synthetic mimics of antimicrobial peptides
• ISSN: 1075-2617; 1099-1387; 1099-1387
• DOI: 10.1002/psc.3117

The present study describes the synthesis and biological studies of a small series of head-to-tail cyclic tetrapeptides of the general structure c(Lys-β -Xaa-Lys) containing one lipophilic β -amino acid and Lys, Gly, Ala, or Phe as the Xaa residue in the sequence. The peptides were investigated for antimicrobial activity against gram-positive and gram-negative reference strains and 30 multiresistant clinical isolates including strains with extended spectrum β-lactamase-carbapenemase (ESBL-CARBA) production. Toxicity was determined against human red blood cells. The most potent peptides showed high activity against the gram-positive clinical isolates with minimum inhibitory concentrations of 4-8 μg/mL and low haemolytic activity. The combination of high antimicrobial activity and low toxicity shows that these cyclic tetrapeptides containing lipophilic β -amino acids form a valuable scaffold for designing novel antimicrobial agents.