Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity

Johannes Zuegg, Craig Muldoon, George Adamson, Declan McKeveney, Giang Le Thanh, Rajaratnam Premraj, Bernd Becker, Mu Cheng, Alysha G. Elliott, Johnny X. Huang, Mark S. Butler, Megha Bajaj, Joachim Seifert, Latika Singh, Nicola F. Galley, David I. Roper, Adrian J. Lloyd, Christopher G. Dowson, Ting-Jen Cheng, Wei-Chieh Cheng, Dieter Demon, Evelyne Meyer, Wim Meutermans () and Matthew A. Cooper ()
Additional contact information
Johannes Zuegg: Institute for Molecular Bioscience, The University of Queensland
Craig Muldoon: Alchemia Ltd
George Adamson: Alchemia Ltd
Declan McKeveney: Alchemia Ltd
Giang Le Thanh: Alchemia Ltd
Rajaratnam Premraj: Alchemia Ltd
Bernd Becker: Alchemia Ltd
Mu Cheng: Institute for Molecular Bioscience, The University of Queensland
Alysha G. Elliott: Institute for Molecular Bioscience, The University of Queensland
Johnny X. Huang: Institute for Molecular Bioscience, The University of Queensland
Mark S. Butler: Institute for Molecular Bioscience, The University of Queensland
Megha Bajaj: Institute for Molecular Bioscience, The University of Queensland
Joachim Seifert: Alchemia Ltd
Latika Singh: Alchemia Ltd
Nicola F. Galley: School of Life Science, University of Warwick
David I. Roper: School of Life Science, University of Warwick
Adrian J. Lloyd: School of Life Science, University of Warwick
Christopher G. Dowson: School of Life Science, University of Warwick
Ting-Jen Cheng: Genomics Research Center, Academia Sinica
Wei-Chieh Cheng: Genomics Research Center, Academia Sinica
Dieter Demon: Faculty of Veterinary Medicine, Laboratory of Biochemistry, Ghent University
Evelyne Meyer: Faculty of Veterinary Medicine, Laboratory of Biochemistry, Ghent University
Wim Meutermans: Alchemia Ltd
Matthew A. Cooper: Institute for Molecular Bioscience, The University of Queensland

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract The rapid rise of multi-drug-resistant bacteria is a global healthcare crisis, and new antibiotics are urgently required, especially those with modes of action that have low-resistance potential. One promising lead is the liposaccharide antibiotic moenomycin that inhibits bacterial glycosyltransferases, which are essential for peptidoglycan polymerization, while displaying a low rate of resistance. Unfortunately, the lipophilicity of moenomycin leads to unfavourable pharmacokinetic properties that render it unsuitable for systemic administration. In this study, we show that using moenomycin and other glycosyltransferase inhibitors as templates, we were able to synthesize compound libraries based on novel pyranose scaffold chemistry, with moenomycin-like activity, but with improved drug-like properties. The novel compounds exhibit in vitro inhibition comparable to moenomycin, with low toxicity and good efficacy in several in vivo models of infection. This approach based on non-planar carbohydrate scaffolds provides a new opportunity to develop new antibiotics with low propensity for resistance induction.

Date: 2015
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DOI: 10.1038/ncomms8719

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