Targeting metalloenzymes: a strategy that works.
Faced with a wealth of antibacterial drug discovery targets as a result of bacterial genomics, we need to carefully select which ones to work with. Choosing bacterial metalloenzymes is one possible approach that can increase the probability of success. Metalloenzymes can be identified through specific motif searches of bacterial genomes. Current state-of-the-art medicinal chemistry allows for the design of inhibitor libraries targeting metalloenzymes and the efficient optimization of leads identified. This approach has been successfully applied to the discovery of in vivo active antibacterial agents that are inhibitors of bacterial peptide deformylase and UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase. Other bacterial metalloenzymes are open to the same approach.
White
Richard J
RJ
Vicuron Pharmaceuticals, 34790 Ardentech Court, Fremont, CA 94555, USA.
Margolis
Peter S
PS
Trias
Joaquim
J
Yuan
Zhengyu
Z
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors / Q000737:chemistry; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004798:Enzymes / Q000737:chemistry*; D008667:Metalloproteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D004798:Enzymes; D008667:Metalloproteins; D009097:Multienzyme Complexes; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase; C084507:peptide deformylase; D019747:Aldose-Ketose Isomerases