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Nat Commun. 2015 Jul 21;6:7719. doi: 10.1038/ncomms8719.

Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity.

Author information

1
1] Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia [2] Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
2
Alchemia Ltd, PO Box 4851, Eight Mile Plains, Brisbane, Queensland 4113, Australia.
3
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
4
School of Life Science, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
5
Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Taipei 115, Taiwan.
6
Faculty of Veterinary Medicine, Laboratory of Biochemistry, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.

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.

PMID:
26194781
PMCID:
PMC4530474
DOI:
10.1038/ncomms8719
[Indexed for MEDLINE]
Free PMC Article

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