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FEBS Lett. 2012 Nov 30;586(23):4223-7. doi: 10.1016/j.febslet.2012.10.027. Epub 2012 Oct 26.

Transient kinetics of aminoglycoside phosphotransferase(3')-IIIa reveals a potential drug target in the antibiotic resistance mechanism.

Author information

1
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.

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.

PMID:
23108046
PMCID:
PMC3510435
DOI:
10.1016/j.febslet.2012.10.027
[Indexed for MEDLINE]
Free PMC Article

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