A Battle Between Pathogens and Medicinal Chemistry: Tetracycline Generations and the Evolution of Resistance Mechanisms

Abstract

Tetracyclines have been utilized extensively for more than 70 years which has led to the development of resistance by pathogenic bacteria. New generations of tetracyclines have been produced in response to this resistance. Since tetracyclines are broad-spectrum antibiotic used to treat different bacterial infections, it is essential for clinical use. Synthetic strategies have been developed to modify the drug in response to resistance. Currently, three different third-generation tetracyclines are on the market and are sold as Tygacil, Nuxga and Xerara. These tetracyclines are much more effective than previous generations due to an increased affinity towards the target ribosome and an ability to evade bacterial efflux proteins. However, at least for the case of Tygacil, which has been tested in vitro, these tetracyclines might be susceptible to degradation by the enzyme tetracycline monooxygenase (TetX), which modifies the antibiotics to 11a-hydroxytetracycline. The TetX reaction product is unstable at physiological pH and decomposes before it can interact with the bacterial ribosome to inhibit protein synthesis. Understanding details about the catalytic mechanism of TetX could lead to the development of inhibitors of the enzyme to provide an additional strategy to combat antibiotic resistance. The current review will detail the chemical features of each generation of tetracyclines, the biochemical basis for tetracycline treatment and the mechanisms by which bacteria are able to resist the drugs. It will end with a discussion of TetX and an activity assay developed to study the enzyme.