Halting Tuberculosis in Its Tracks: Advances and Strategies for Discovering Therapeutic Targets in <i>Mycobacterium tuberculosis</i>

Tuberculosis is a global emergency. Despite two decades of intense research to understand and cure the disease, biological uncertainties prevail and hamper the therapeutic progress. Increasing incidences of multidrug-resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis strains further complicate tuberculosis control. Modern research, therefore, focuses on development of new antitubercular drugs to treat drug-resistant tuberculosis and shorten the duration of the standard chemotherapy. Fortunately, the recent accelerated approval of delamanid and bedaquiline for use in MDR and XDR tuberculosis has reinvigorated antitubercular research. Although progresses in tuberculosis drug discovery are being made following the availability of M. tuberculosis genome and progressions in molecular biology, novel drug targets and leads are continuously required to strengthen the tuberculosis therapeutic pipeline. Discovery of new targets has eventually promoted tuberculosis therapy, and will keep paving the foundation for generating the future wave of tuberculosis drug leads. This review summarizes important M. tuberculosis drug targets such as F₁/F₀ ATP synthase, isocitrate lyase, β-ketoacyl-ACP synthases KasA and KasB, QcrB, and mycobactin biosynthesis enzymes MbtA and MbtI, and drugs under preclinical and clinical development stages that aim at making drug discovery breakthroughs. It also discusses the strategies that entail discovery of new mycobacterial therapeutic determinants and provide ideas for development of more efficient drugs. The article comprehensively provides a better understanding of M. tuberculosis drug targets, along with opening new ventures for tuberculosis control and treatment.