Current possibilities and unresolved issues of drug target validation in Mycobacterium tuberculosis

Target driven drug discovery is a long and arduous task requiring a huge investment of time, energy and resources. Therefore, it is very important to select targets which provide the maximum chance of obtaining inhibitors that will be efficacious in animal models and finally in tuberculosis (TB) patients.

The article discusses the necessity for new targets in Mycobacterium tuberculosis (Mtb) drug discovery and how the functional redundancy of putative targets in Mtb adds a new dimension to the complexity of validation. The article also reviews survival kinetics using conditional knockout (KO) or knockdown (KD) strains and discusses how this has provided crucial information on target vulnerability. Furthermore, the article also comments on how the chemical validation of new targets using specific inhibitors has greatly supplemented the genetic validation efforts.

Because of complexity of pathogenesis of TB, the putative drug targets need to be validated under multiple physiological conditions. Target protein depletion can mimic chemical inhibition and, therefore, will be a valuable tool in predicting the vulnerability of a target. Conditional KO or KD makes it possible to study the phenotypes of Mtb strains under a variety of physiological states. The phenotype of these strains should also be tested in animal models which mimic human TB more closely. Finally, inhibitors with confirmed mode of action can be important tools for validating Mtb drug targets.