Structure and function of the Mur enzymes: development of novel inhibitors.
One of the biggest challenges for recent medical research is the continuous development of new antibiotics interacting with bacterial essential mechanisms. The machinery for peptidoglycan biosynthesis is a rich source of crucial targets for antibacterial chemotherapy. The cytoplasmic steps of the biosynthesis of peptidoglycan precursor, catalysed by a series of Mur enzymes, are excellent candidates for drug development. There has been growing interest in these bacterial enzymes over the last decade. Many studies attempted to understand the detailed mechanisms and structural features of the key enzymes MurA to MurF. Only MurA is inhibited by a known antibiotic, fosfomycin. Several attempts made to develop novel inhibitors of this pathway are discussed in this review. Three novel inhibitors of MurA were identified recently. 4-Thiazolidinone compounds were designed as MurB inhibitors. Many phosphinic acid derivatives and substrate analogues were identified as inhibitors of the MurC to MurF amino acid ligases.
El Zoeiby
Ahmed
A
Centre de Recherche sur la Fonction, Structure et Ingénierie des Protéines, Faculté de Médecine, Pavillon Charles-Eugène Marchand, Université Laval, Ste-Foy, Québec, Canada, G1K 7P4.
Sanschagrin
François
F
Levesque
Roger C
RC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002237:Carbohydrate Dehydrogenases / Q000037:antagonists & inhibitors / Q000737:chemistry; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D005798:Genes, Bacterial; D008025:Ligases / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000737:chemistry; D010457:Peptidoglycan / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D010457:Peptidoglycan; D002237:Carbohydrate Dehydrogenases; C023215:UDP-N-acetylmuramate dehydrogenase; D019883:Alkyl and Aryl Transferases; C022566:UDP-N-acetylglucosamine 1-carboxyvinyltransferase; D008025:Ligases; D010453:Peptide Synthases; C023229:UDP-N-acetylmuramoyl-alanine synthetase; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase