Journal article
Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria
T Velkov, A Gallardo-Godoy, JD Swarbrick, MAT Blaskovich, AG Elliott, M Han, PE Thompson, KD Roberts, JX Huang, B Becker, MS Butler, LH Lash, ST Henriques, RL Nation, S Sivanesan, MA Sani, F Separovic, H Mertens, D Bulach, T Seemann Show all
Cell Chemical Biology | CELL PRESS | Published : 2018
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..
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Awarded by National Institutes of Health
Funding Acknowledgements
J.L. and T.V. are supported by research grants from the National Institute of Allergy and Infectious Diseases of the NIH (R01A1070896 and R01AI079330). J.L. and T.V. are also supported by the Australian National Health and Medical Research Council (NHMRC). J.L. is an Australian NHMRC Senior Research Fellow. T.V. is an Australian NHMRC Industry Career Development Level 1 Research Fellow and M.A.C. is an NHMRC Principal Research Fellow (APP1059354). Research conducted by A.G.-G., M.S.B., A.G.E., S.T.H., J.X.H., M.A.T.B., and M.A.C. was supported by NHMRC grants APP1005350 and APP1045326, and research by A.G.-G., M.S.B., A.G.E., S.T.H., J.X.H., M.A.T.B., M.A.C., and L.L. by NIH grant R21AI098731/4R33AI098731-03. M.S.B., J.X.H., and M.A.T.B. were also supported by a Wellcome Trust Seeding Drug Discovery Award (094977/Z/10/Z). S.T.H. is the recipient of a Discovery Early Career Researcher Award (DE120103152), awarded by the Australian Research Council. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the NIH.