Challenges and Advances in TB Drug Discovery

In this chapter, we provide a comprehensive review of the recent developments and challenges associated with tuberculosis drug discovery. The chapter begins with an overview of the global TB burden with an emphasis on the high-burden countries such as India and the probable reasons associated with high disease burden. We have discussed the targets for the WHO End TB Strategy along with the requirements to achieve them. The chapter further provides an insight into the major obstacles of TB control, the problems associated with the current chemotherapy, the need for new anti-TB drugs and expectations from an ideal TB therapy. The chapter also provides a comprehensive review of the candidate drugs in the TB drug clinical pipeline with description of their identification, mechanistic action and in vitro and in vivo efficacy data along with clinical trial progress. We then provide details about the commonly employed approaches like whole cell phenotypic approach, target-based virtual screening and repurposing of drugs for TB drug discovery along with the advantages and major challenges associated with these approaches. In this regard, the success of whole cell-based phenotypic screening has been highlighted in view of discovery of the two recently FDA-approved anti-TB drugs, namely, bedaquiline and delamanid. The chapter also deals with another promising strategy for TB drug discovery based on rational drug design with a focus on some of the leads identified by this approach. We have also emphasized the recent advancements towards newer approaches like antisense RNA-based therapeutics, use of natural products, gene-editing tools such as CRISPR-CAS system and immunotherapy for the development of anti-TB molecules. Besides, the chapter also describes the development of methods to enhance the bioavailability of drugs such as novel delivery systems like nanoparticles/liposomes and devices for sustained release.