Evolution of Antibiotic Resistance Mechanisms: The Case of Tetracycline Degradation by Flavin Monooxygenases

This chapter provides a history of tetracycline antibiotics by highlighting synthetic modification of the drug made in response to bacterial resistance. An emerging mechanism of antibiotic resistance involving enzymatic degrading of the drug by tetracycline monooxygenase (TetX) is described to raise awareness of a contemporary problem in medicine.

Bacterial resistance to tetracycline developed soon after it was introduced to the clinic. Two prevalent resistance mechanisms involve the action of proteins to either directly protect the ribosome or to pump tetracycline out of the cell through efflux. Syntenic modifications of tetracycline have occurred in response to bacterial resistance. Currently, three third-generation tetracyclines are on the market (Tygacil, Nuxga and Xerara). These drugs show an increased affinity towards the target ribosome and an ability to evade efflux. However, in vitro studies of Tygacil demonstrated these tetracyclines are susceptible to enzymatic degradation by the flavin dependent enzyme TetX. Understanding details about the catalytic mechanism of TetX could lead to the development of inhibitors to combat antibiotic resistance. To this end a TetX activity assay is described that allows for a quick determination its kinetic parameters. Data collected using the assay agree well with that previously obtained with more laborious methods. This dawns a new era of investigation to combat tetracycline resistance.