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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology
  • Drug Resistance, Microbial
  • Kanamycin / metabolism
  • Kanamycin / pharmacology
  • Kanamycin Kinase / metabolism*
  • Kinetics


  • Anti-Bacterial Agents
  • Kanamycin
  • Kanamycin Kinase