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

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

Cell chemical biology (2018-02-06)
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 Seemann, Jeremy Owen, Jian Li, Matthew A Cooper
ABSTRACT

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.

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