**3. Tuberculosis (TB)**

TB continues to be threat to public health enlisted among top 10 causes of death worldwide. The causative agent, bacillus *M.tb,* singly kills more people than HIV/ AIDS pathogen does. It is one of the momentous disquietude since two decades when the World Health Organization declared it a global health emergency. With the rise of antibiotic resistance in *M.tb*, the causative agent of TB has made it immensely difficult to control the disease with the already existing anti-TB chemotherapy. The need of hour is to develop effective drugs with novel mechanism(s) of action so as to curb the drug resistance. The development of novel chemical entities requires >10 years of research, with high-risk investment to become available commercially. TB spreads are easier as it is contracted by inhaling droplets of infection expelled in air from TB patient. TB mostly affects lungs (pulmonary TB) but can also affect all other sites (extrapulmonary TB) sparing only nail and hair. About a quarter of the world's population is infected with *M. TB*. TB continues to be a major cause of morbidity and mortality, primarily in low-income and middle-income countries [21]. In 2019, an estimated 10.0 million (range, 8.9–11.0 million) people fell ill with TB—in HIV-negative people, 1.2 million (range; 1.1–1.3 million) TB deaths, and 208,000 deaths (range; 177,000–242,000) among HIV-positive people. Men (aged ≥15 years) accounted for 56% of the people who developed TB in 2019; women accounted for 32%; and children (aged <15 years) for 12%. Among all those affected, 8.2% were people living with HIV (World Tb report 2020). Eight countries accounted for two-thirds of the global total: India is a leading country, which covers (26%) of TB burden, Indonesia (8.5%), China (8.4%), the Philippines (6.0%), Pakistan (5.7%), Nigeria (4.4%), Bangladesh (3.6%), and South Africa (3.6%). In 2020, we have lost count of TB-affected people and deaths due to COVID-19 pandemic and the previous efforts against TB as well. More DOTS centers got malfunctional due to medical emergency, and many children missed the BCG vaccination. Till emergence of drug-resistant strains, TB was successfully treated using

chemotherapy which comprised of four first-line anti-TB drugs: isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB). Then, second-line drug regimens were developed, which consisted of aminoglycosides (Kanamycin, amikacin), capreomycin, cycloserin, para-aminosalicylic acid, thioamides (ethionamide (ETH), prothionamide), and fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) [22]. But multidrug-resistant, extremely drug-resistant, and total drug-resistant strains emerged and the conventional drug regimens started to lose their efficacy. Incomplete, inadequate, and wrong prescription of the standard therapy are responsible for the emergence of drug-resistant strains of *M. TB* [23]. Multidrug-resistant TB (MDR-TB) is defined as resistance to at least isoniazid and rifampicin. Extensively drug-resistant TB (XDR-TB), which causes more severe disease manifestations, is not only resistant to isoniazid and rifampicin but also resistant to any fluoroquinolone and injectable second-line aminoglycosides. When the pathogen becomes resistant to all first- and second-line anti-TB drugs, totally drug-resistant (TDR) is said to have developed. TB existing drugs are slow to eradicate the pathogen in patients and the intrinsic resistance systems of *M.tb* have evolved to make the present antibiotics ineffective [24]. Moreover, long-term chemotherapy with frequent dosage arises chances of drug toxicity; therefore, urge for new drugs is on rise to shorten the TB treatment. The birth of drug repurposing in TB treatment was marked upon global resurgence of TB, especially in New York City during the late 1980s where the infection had almost quadrupled and more than one-half of cases were resistant to INH and RIF (i.e., MDR). Like cancers or other diseases, drug repurposing approach for TB is based on various approaches such as host-directed targets, structure-based drug targets, *in silico*-based approach, and combinatorial drug therapy approach. In this book chapter, we provide an overview of various approaches that aid drug repurposing for TB. We also discuss the targets and clinical trials carried out for the repurposing strategy.
