Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity

Zuegg, Johannes, Muldoon, Craig, Adamson, George, McKeveney, Declan, Le Thanh, Giang, Premraj, Rajaratnam, Becker, Bernd, Cheng, Mu, Elliott, Alysha G., Huang, Johnny X., Butler, Mark S., Bajaj, Megha, Seifert, Joachim, Singh, Latika, Galley, Nicola F., Roper, David I., Lloyd, Adrian J., Dowson, Christopher G., Cheng, Ting-Jen, Cheng, Wei-Chieh, Demon, Dieter, Meyer, Evelyne, Meutermans, Wim and Cooper, Matthew A. (2015) Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity. Nature Communications, 6 1-11. doi:10.1038/ncomms8719

Author Zuegg, Johannes
Muldoon, Craig
Adamson, George
McKeveney, Declan
Le Thanh, Giang
Premraj, Rajaratnam
Becker, Bernd
Cheng, Mu
Elliott, Alysha G.
Huang, Johnny X.
Butler, Mark S.
Bajaj, Megha
Seifert, Joachim
Singh, Latika
Galley, Nicola F.
Roper, David I.
Lloyd, Adrian J.
Dowson, Christopher G.
Cheng, Ting-Jen
Cheng, Wei-Chieh
Demon, Dieter
Meyer, Evelyne
Meutermans, Wim
Cooper, Matthew A.
Title Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity
Formatted title
Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2015-07-21
Sub-type Article (original research)
DOI 10.1038/ncomms8719
Open Access Status DOI
Volume 6
Start page 1
End page 11
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2016
Language eng
Formatted 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.
Keyword Cell wall biosynthesis
Staphylococcus aureus
Bacterial transglycosylase
Crystal structure
Peptidoglycan biosynthesis
Antimicrobial resistance
Vancomycin resistance
Antibiotic resistance
Escherichia coli
Lipid II
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 5 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
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