Phenothiazines as anti-tubercular agents: mechanistic insights and clinical implications

Introduction: Tuberculosis (TB) chemotherapy has been rendered ineffective by the emergence of multi-drug resistant (MDR), extensively drug resistant (XDR) and totally drug resistant strains reinforcing the need for the development of new drugs as a global health priority. Reconsidering phenothiazines for the improvement of TB chemotherapy seems to be a rational option especially in view of their role as inhibitors of type II NADH dehydrogenase, a key component of respiratory chain of Mycobacterium tuberculosis, thus raising the speculation that they can be effective against latent TB as well. Areas covered: This article offers a detailed description of the chemotherapeutic efficacy of phenothiazine compounds against susceptible, drug resistant and latent TB. Furthermore, their clinical implications and molecular mechanisms of action have been reviewed extensively. Expert Opinion: Phenothiazines are currently being evaluated for the treatment of TB and have been shown to be effective against M. tuberculosis through a number of in vitro, ex vivo and in vivo studies. In addition, recent clinical studies have implicated their role in the treatment of MDR/XDR TB also. Therefore, phenothiazines, particularly thioridazine, hold great potential to be considered as safe and effective antimycobacterial agents in near future.