Tuberculosis (TB) is highly dangerous due to the development of resistance to first-line drugs. Moreover, Mycobacterium tuberculosis (Mtb) has also developed resistance to newly approved antitubercular drug bedaquiline. This necessitates the search for drugs acting on newer molecular targets. The energy metabolism of mycobacteria is the prime focus for the discovery of novel antitubercular drugs. Targeting type-2 NADH dehydrogenase (NDH-2) involved in the production of respiratory ATP could, therefore, be effective in treating the disease. Areas covered: This review describes the energetics of mycobacteria and the role of NDH-2 in ATP synthesis. Special attention has been given for genetic and chemical validations of NDH-2 as a molecular target. The reported kinetics and crystal structures of NDH-2 have been given in detail for better understanding of the enzyme. Expert opinion: NDH-2 is an essential enzyme for ATP synthesis and has a potential role in dormancy and persistence of Mtb. The human counterpart lacks this enzyme and hence NDH-2 inhibitors could have more clinical importance. Phenothiazines are potent inhibitor of NDH-2 and are effective against both drug-susceptible and drug-resistant Mtb. Thus, it is highly desirable to optimize phenothiazine class of compounds for the development of next generation anti-TB drugs.
The incidence of Tuberculosis (TB) is baffling in developing countries due to the increase in multidrug-resistant and extensively drug-resistant TB. Therefore, drugs acting through different mechanisms are in dire need to counter the resistant strains. Various chemical scaffolds are being investigated against tuberculosis, among them the molecules containing phenothiazine nucleus are found to be more effective against both susceptible and resistant strains of M. tuberculosis. In addition, the efficacy of first-line drugs has been found to be enhanced on supplementary treatment with phenothiazines. The present review provides an overview of the phenothiazine based molecules which were investigated during the last ten years for their anti-tubercular activity.
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