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.
Highlights
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
We synthesized a small library of compounds by replacing the phosphoglycerate/phosphate moieties (G, Fig. 1) with simpler lipophilic substituents and changing the orientation and nature of ring F
Using moenomycin A and previously reported GT inhibitors[27,28], we designed and synthesized a small library of disaccharide-based compounds with a smaller, more drug-like, hydrophobic tail[29]. These compounds showed good in vitro antibacterial activity but had unfavourable physicochemical properties that limited their in vivo application
Summary
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. 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. GTs catalyse the polymerization of lipid II disaccharide units, forming a long chain of alternating b-1,4-linked N-acetylglucosamines and N-acetylmuramic acid, leading to a linear glycan chain and the release of undecaprenylpyrophosphate carrier[1,2,3] These carbohydrate chains are further crosslinked by TP enzymes, forming linkages between the peptide chain and the D-alanine of a neighboring unit (Fig. 1). The lack of a specific resistance mechanism and the paucity of antibiotics that mimic the carbohydrate portion of bacterial lipid II suggest that direct GT inhibition remains an attractive strategy for the development of novel antibacterial agents with low potential for resistance development. Moenomycin A is a highly functionalized pentasaccharide attached via a phosphoglycerate linkage to a polyprenyl chain[22] (Fig. 1) that binds competitively to GT enzymes by mimicking the disaccharide–pyrophosphate–prenol linkage of the donor lipid
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