Prospects for novel inhibitors of peptidoglycan transglycosylases

Abstract

The lack of novel antimicrobial drugs under development coupled with the increasing occurrence of resistance to existing antibiotics by community and hospital acquired infections is of grave concern. The targeting of biosynthesis of the peptidoglycan component of the bacterial cell wall has proven to be clinically valuable but relatively little therapeutic development has been directed towards the transglycosylase step of this process. Advances towards the isolation of new antimicrobials that target transglycosylase activity will rely on the development of the enzymological tools required to identify and characterise novel inhibitors of these enzymes. Therefore, in this article, we review the assay methods developed for transglycosylases and review recent novel chemical inhibitors discovered in relation to both the lipidic substrates and natural product inhibitors of the transglycosylase step.

Keywords: Antibiotic; Discovery; Inhibitor; Peptidoglycan; Transglycosylase.

Graphical abstract

Fig. 1

Schematic diagram of the transglycoylase active site showing doner and acceptor sites. Residue numbers in the acceptor sites refer to those determined for S. aureus monofunctional transglycosylase in relation to lipid II analogue as described by Huang et al. .

Fig. 2

Schematic of the main techniques currently available to assay transglycosylase activity allowing inhibitor discovery as discussed in Section 2. A cartoon representation of a typical reaction trace is shown for each technique and section numbers corresponding to the text are included.

Fig. 3

The structure of Moenomycin A, the only known potent inhibitor for bacterial transglycosylases. The region highlighted in blue is the minimal inhibitory pharmacophore, which is often used as a scaffold for the design of new potential inhibitors (discussed in Section 3.1).

Fig. 4

The structure of vancomycin and its derivative chlorobiphenyl vancomycin (CBP-V), which showed antibacterial activity against vancomycin-resistant Enterococci (VRE) (discussed in Section 3.5).