Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity.

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.

A versatile synthetic approach toward diversity libraries using monosaccharide scaffolds.

The pyranose scaffold is unique in its ability to position pharmacophore substituents in various ways in 3D space, and unique pharmacophore scanning libraries could be envisaged that focus on scanning topography rather than diversity in the type of substituents. Approaches have been described that make use of amine and acid functionalities on the pyranose scaffolds to append substituents, and this has enabled the generation of libraries of significant structural diversity. Our general aim was to generate libraries of pyranose-based drug-like mimetics, where the substituents are held close to the scaffold, in order to obtain molecules with better defined positions for the pharmacophore substituents. Here we describe the development of a versatile synthetic route toward peptide mimetics build on 2-amino pyranose scaffolds. The method allows introduction of a wide range of substituent types, it is regio- and stereospecific, and the later diversity steps are performed on solid phase. Further, the same process was applied on glucose and allose scaffolds, in the exemplified cases, and is likely adaptable to other pyranose building blocks. The methods developed in this work give access to molecules that position the three selected binding elements in various 3D orientations on a pyranose scaffold and have been applied for the production of a systematically diverse library of several hundred monosaccharide-based mimetics.

Targeting the forgotten transglycosylases.

Forty years ago, moenomycin was reported as a representative of a novel natural product class with strong antibacterial activity against Gram-positive organisms. Moenomycin was developed as an antimicrobial growth promoter in animal feeds. Mechanistically, moenomycin acts via inhibition of the transglycosylation process at the final stage of the peptidoglycan biosynthesis, in particular through binding directly to the transglycosylase enzymes, thereby preventing polymerisation of lipid II into linear peptidoglycan. Despite moenomycin's success, no developments of direct transglycosylase enzyme inhibitors were reported for over 30 years, probably due to the complexities and uncertainties surrounding the transglycosylation process, in particular the number of enzymes involved in the process and their specific roles. The development of better research tools and an improved understanding of the transglycosylation process, together with the increasing threat presented by multidrug-resistant bacteria, have led to a resurfacing of interest in targeting the forgotten transglycosylases. In addition, several new generation glycopeptides in clinical development inhibit the transglycosylation process, adding further value to the approach. In this paper, we summarise some of the developments in the area of transglycosylase inhibitors over the last 10 years.