Genetic Strategies for Identifying New Drug Targets.

Genetic strategies have yet to come into their own as tools for antibiotic development. While holding a lot of initial promise, they have only recently started to bear fruit in the quest for new drug targets. An ever-increasing body of knowledge is showing that genetics can lead to significant improvements in the success and efficiency of drug discovery. Techniques such as high-frequency transposon mutagenesis and expression modulation have matured and have been applied successfully not only to the identification and characterization of new targets, but also to their validation as tractable weaknesses of bacteria. Past experience shows that choosing targets must not rely on gene essentiality alone, but rather needs to incorporate knowledge of the system as a whole. The ability to manipulate genes and their expression is key to ensuring that we understand the entire set of processes that are affected by drug treatment. Focusing on exacerbating these perturbations, together with the identification of new targets to which resistance has not yet occurred--both enabled by genetic approaches--may point us toward the successful development of new combination therapies engineered based on underlying biology.