Targeting Energy Metabolism in Mycobacterium tuberculosis , a New Paradigm in Antimycobacterial Drug Discovery

Abstract

Drug-resistant mycobacterial infections are a serious global health challenge, leading to high mortality and socioeconomic burdens in developing countries worldwide. New innovative approaches, from identification of new targets to discovery of novel chemical scaffolds, are urgently needed. Recently, energy metabolism in mycobacteria, in particular the oxidative phosphorylation pathway, has emerged as an object of intense microbiological investigation and as a novel target pathway in drug discovery. New classes of antibacterials interfering with elements of the oxidative phosphorylation pathway are highly active in combating dormant or latent mycobacterial infections, with a promise of shortening tuberculosis chemotherapy. The regulatory approval of the ATP synthase inhibitor bedaquiline and the discovery of Q203, a candidate drug targeting the cytochrome bc1 complex, have highlighted the central importance of this new target pathway. In this review, we discuss key features and potential applications of inhibiting energy metabolism in our quest for discovering potent novel and sterilizing drug combinations for combating tuberculosis. We believe that the combination of drugs targeting elements of the oxidative phosphorylation pathway can lead to a completely new regimen for drug-susceptible and multidrug-resistant tuberculosis.

Shortening Buruli Ulcer Treatment with Combination Therapy Targeting the Respiratory Chain and Exploiting Mycobacterium ulcerans Gene Decay

“…The electron transport chain (ETC) and oxidative phosphorylation have recently proven to be vulnerable targets for exciting new drugs for tuberculosis (TB) (9). The ATP synthase inhibitor bedaquiline (BDQ) has significant treatment-shortening effects in mouse TB models and is a core component of novel treatment-shortening regimens for both drug-susceptible and multidrug-resistant TB (10)(11)(12)(13)(14)(15)(16).…”

“…The cytochrome bc 1 :aa 3 complex inhibitor Q203 has efficacy in mouse TB models and is poised to enter phase 2 trials in TB patients (17,18). Clofazimine is reduced by NDH-2 (type II dehydrogenase), which is the point of entry of electrons into the respiratory chain (9,19). Another exciting development is the recent in vitro finding of substantial synergistic effects of CFZ with either BDQ or Q203 against Mycobacterium tuberculosis and optimal effects when all 3 inhibitors are combined (20).…”

Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity

“…[5] Importantly, while common among bacteria and protozoan parasites, these enzymes are absent from the mammalian genome, which further highlights their potential as drug targets. [6] A well-validated, specific Ndh-2 inhibitor would both provide a novel tool to study Ndh-2 function and enable preclinical pharmacological validation of Ndh-2 as a target for TB therapy.…”

in silico Quest Guided by Physico-Chemical Descriptors of Bedaquiline for New Scaffolds with Potential Inhibitory Capacity against Homology Model of Mycobacterium F1F0 ATP Synthase

“…With most of the drugs in use are rendered ineffective or less effective due to emergence of drug resistant strains, developing new strategies and finding new targets is a pressing need to mitigate the risk of drug resistance [6,7]. One such pathway that has garnered lot of attention lately is energy metabolism in MTB and this obviously is credited to the US FDA approval for bedaquiline, reported to inhibit F1F0 ATP synthase [8,9]. Replicating or non-replicating tuberculi need to maintain threshold levels of ATP for their survival.…”