title: Transient kinetics of aminoglycoside phosphotransferase(3')-IIIa reveals a potential drug target in the antibiotic resistance mechanism.
abstract: Aminoglycoside phosphotransferases are bacterial enzymes responsible for the inactivation of aminoglycoside antibiotics by O-phosphorylation. It is important to understand the mechanism of enzymes in order to find efficient drugs. Using rapid-mixing methods, we studied the transient kinetics of aminoglycoside phosphotransferase(3')-IIIa. We show that an ADP-enzyme complex is the main steady state intermediate. This intermediate interacts strongly with kanamycin A to form an abortive complex that traps the enzyme in an inactive state. A good strategy to prevent the inactivation of aminoglycosides would be to develop uncompetitive inhibitors that interact with this key ADP-enzyme complex.
authors.affiliation: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé (CPBS), UMR 5236 CNRS, University Montpellier I & II, 1919 Route de Mende, 34293 Montpellier Cedex 5, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Lallemand
authors.forename: Nadia
authors.initials: N
authors.lastname: Leban
authors.forename: Simone
authors.initials: S
authors.lastname: Kunzelmann
authors.forename: Laurent
authors.initials: L
authors.lastname: Chaloin
authors.forename: Engin H
authors.initials: EH
authors.lastname: Serpersu
authors.forename: Martin R
authors.initials: MR
authors.lastname: Webb
authors.forename: Tom
authors.initials: T
authors.lastname: Barman
authors.forename: Corinne
authors.initials: C
authors.lastname: Lionne
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D007612:Kanamycin / Q000378:metabolism / Q000494:pharmacology; D019868:Kanamycin Kinase / Q000378:metabolism*; D007700:Kinetics
chemical_list: D000900:Anti-Bacterial Agents; D007612:Kanamycin; D019868:Kanamycin Kinase