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.
Halliday
Judy
J
Alchemia Limited, 3 Hi-Tech Court, Eight Mile Plains, Brisbane Technology Park, Qld 4113, Australia.
McKeveney
Declan
D
Muldoon
Craig
C
Rajaratnam
Premraj
P
Meutermans
Wim
W
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D002473:Cell Wall / Q000187:drug effects / Q000201:enzymology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010457:Peptidoglycan / Q000096:biosynthesis; D046928:Peptidoglycan Glycosyltransferase / Q000037:antagonists & inhibitors*
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010457:Peptidoglycan; D046928:Peptidoglycan Glycosyltransferase