Tuberculosis (TB) is a leading infectious disease that caused the deaths of a total of 1.5 million people in 2020 and is one of the top causes of death globally. India is a country with the highest TB burden, and it may affect all age groups. It is caused by the Mycobacterium tuberculosis bacteria, an intracellular pathogen, and its multidrug and extensively drug-resistant strains, which continue to emerge and spread, resulting in the deadliest infectious disease. After a gap of more than 40 years, the FDA approvals over the past decade of three second-line anti-TB drugs, bedaquiline, delamanid, and pretomanid, have been major forward steps in the management of drug-resistant-TB (DR-TB). Many medicinal plants such as Zanthoxylum leprieurii, Lantana camara, and Cryptolepis sanguinolenta have extensive therapeutic potential and represent a prospective option to fight against DR-TB. Some novel compounds are in the early clinical trial phases such as DprE1 inhibitors TBA-7371 and BTZ-043, and many others that are showing promising futures. This review describes DR-TB and its current chemotherapy guidelines including novel and repurposed drugs that are included in the anti-TB regimens, medicinal plants that have therapeutic potential for the development of drug-hit candidates, drugs that are currently in clinical development, host-directed therapy, and new drug delivery systems to better understand the novel therapeutic approaches that are currently being studied for the efficacious and safe management of DR-TB, a worldwide health problem.

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