Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria. Issue 4 (19th April 2018)

• Record Type: Journal Article
• Authors: Velkov, Tony; Gallardo-Godoy, Alejandra; Swarbrick, James D.; Blaskovich, Mark. A.T.; Elliott, Alysha G.; Han, Meiling; Thompson, Philip E.; Roberts, Kade D.; Huang, Johnny X.; Becker, Bernd; Butler, Mark S.; Lash, Lawrence H.; Henriques, Sónia Troeira; Nation, Roger L.; Sivanesan, Sivashangarie; Sani, Marc-Antoine; Separovic, Frances; Mertens, Haydyn; Bulach, Dieter; Seemann, Torsten; Owen, Jeremy; Li, Jian; Cooper, Matthew A.
• Is Part Of: Cell chemical biology. Volume 25:Issue 4(2018)
• Page Start: 380
• Page End: 391.e5
• Publication Date: 2018-04-19
• Subjects: polymyxin -- octapeptin -- antibiotic resistance -- extensively drug resistance -- MDR -- XDR -- in vivo -- pharmacokinetics -- infection -- superbug -- novel antibiotic; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.01.005
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: In toto chemical synthesis and pre-clinical evaluation of octapeptins Sequencing and analysis of the octapeptin non-ribosomal biosynthetic cluster Structure-activity and structure-toxicity-based design of novel octapeptins Tailoring of the octapeptin structure to optimize exposure and in vivo activity Abstract : 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.