Mycobacterial drug discovery

Mycobacterium tuberculosis is the causative pathogen of the pulmonary disease tuberculosis. Despite the availability of effective treatment programs, there is a global pursuit of new anti-tubercular agents to respond to the developing threat of drug resistance, in addition to reducing the extensive duration of chemotherapy and any associated toxicity. The route to mycobacterial drug discovery can be considered from two directions: target-to-drug and drug-to-target. The former approach uses conventional methods including biochemical assays along with innovative computational screens, but is yet to yield any drug candidates to the clinic, with a high attrition rate owing to lack of whole cell activity. In the latter approach, compound libraries are screened for efficacy against the bacilli or model organisms, ensuring whole cell activity, but here subsequent target identification is the rate-limiting step. Advances in a variety of scientific fields have enabled the amalgamation of aspects of both approaches in the development of novel drug discovery tools, which are now primed to accelerate the discovery of novel hits and leads with known targets and whole cell activity. This review discusses these traditional and innovative techniques, which are widely used in the quest for new anti-tubercular compounds.