Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity.
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| 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.
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| Authors | 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, Matthew A Cooper |
| Journal | Nature communications (Nat Commun) Vol. 6 Pg. 7719 (Jul 21 2015) ISSN: 2041-1723 [Electronic] England |
| PMID | 26194781 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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