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 trans...

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Bibliographic Details
Published in:Biochemical pharmacology 2006-03, Vol.71 (7), p.957-967
Main Authors: Halliday, Judy, McKeveney, Declan, Muldoon, Craig, Rajaratnam, Premraj, Meutermans, Wim
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Bacteria - drug effects
Bacteria - enzymology
Bacterial cell wall biosynthesis
Cell Wall - drug effects
Cell Wall - enzymology
Drug Design
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Molecular Structure
PBP
Peptidoglycan - biosynthesis
Peptidoglycan Glycosyltransferase - antagonists & inhibitors
TG-domain
Transglycosylase inhibitors
Transglycosylation process
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Summary: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.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2005.10.030