Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria

Tony Velkov, Alejandra Gallardo-Godoy, James D. Swarbrick, Mark A.T. Blaskovich, Alysha G. Elliott, Meiling Han, Philip E. Thompson, Kade D. Roberts, Johnny X. Huang, Bernd Becker, Mark S. Butler, Lawrence H. Lash, Sónia Troeira Henriques, Roger L. Nation, Sivashangarie Sivanesan, Marc Antoine Sani, Frances Separovic, Haydyn Mertens, Dieter Bulach, Torsten SeemannJeremy Owen, Jian Li, Matthew A. Cooper

Research output: Contribution to journalArticleResearchpeer-review

41 Citations (Scopus)


Resistance to the last-resort antibiotic colistin is now widespread and new therapeutics are urgently required. We report the first in toto chemical synthesis and pre-clinical evaluation of octapeptins, a class of lipopeptides structurally related to colistin. The octapeptin biosynthetic cluster consisted of three non-ribosomal peptide synthetases (OctA, OctB, and OctC) that produced an amphiphilic antibiotic, octapeptin C4, which was shown to bind to and depolarize membranes. While active against multi-drug resistant (MDR) strains in vitro, octapeptin C4 displayed poor in vivo efficacy, most likely due to high plasma protein binding. Nuclear magnetic resonance solution structures, empirical structure-activity and structure-toxicity models were used to design synthetic octapeptins active against MDR and extensively drug-resistant (XDR) bacteria. The scaffold was then subtly altered to reduce plasma protein binding, while maintaining activity against MDR and XDR bacteria. In vivo efficacy was demonstrated in a murine bacteremia model with a colistin-resistant P. aeruginosa clinical isolate. Octapeptins are colistin-like lipopeptide antibiotics with activity against multi- and extensively drug-resistant (MDR and XDR) Gram-negative bacteria. We describe the design, synthesis, and early preclinical evaluation of a novel series of octapeptins with superior activity and pharmacokinetics.

Original languageEnglish
Pages (from-to)380-391
Number of pages12
JournalCell Chemical Biology
Issue number4
Publication statusPublished - 19 Apr 2018


  • Antibiotic resistance
  • Extensively drug resistance
  • in vivo
  • Infection
  • MDR
  • Novel antibiotic
  • Octapeptin
  • Pharmacokinetics
  • Polymyxin
  • Superbug
  • XDR

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