Structure, function, and biosynthetic origin of octapeptin antibiotics active against extensively drug-resistant gram-negative bacteria

Velkov T1, Gallardo-Godoy A2, Swarbrick JD3, Blaskovich MAT2, Elliott AG2, Han M4, Thompson PE3, Roberts KD3, Huang JX2, Becker B2, Butler MS2, Lash LH5, Henriques ST2, Nation RL4, Sivanesan S4, Sani M-A6, Separovic F6, Mertens H7, Bulach D8, Seemann T8, Owen J9, Li J4 and Cooper MA2

  1. Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia.
  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
  3. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, 3052 VIC, Australia.
  4. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, 3052 VIC, Australia.
  5. Department of Pharmacology, Wayne State University, School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA.
  6. School of Chemistry, Bio21 Institute, University of Melbourne, Parkville, VIC 3010, Australia.
  7. EMBL, Hamburg, Germany.
  8. Department of Immunology and Microbiology, University of Melbourne, Parkville, VIC 3010, Australia.
  9. School of Biological Sciences, Victoria University, Wellington 6012, New Zealand.

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 multidrug 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 Pseudomonas aeruginosa clinical isolate.