###### Abstract  
New drugs with new mechanisms of action are urgently required to tackle the global tuberculosis epidemic. Following the FDA-approval of the ATP synthase inhibitor bedaquiline (Sirturo(r)), energy metabolism has become the subject of intense focus as a novel pathway to exploit for tuberculosis drug development. This enthusiasm stems from the fact that oxidative phosphorylation (OxPhos) and the maintenance of the transmembrane electrochemical gradient are essential for the viability of replicating and non-replicating _Mycobacterium tuberculosis_ (_M. tb_), the etiological agent of human tuberculosis (TB). Therefore, new drugs targeting this pathway have the potential to shorten TB treatment, which is one of the major goals of TB drug discovery. This review summarises the latest and key findings regarding the OxPhos pathway in _M. tb_ and provides an overview of the inhibitors targeting various components. We also discuss the potential of new regimens containing these inhibitors, the flexibility of this pathway and, consequently, the complexity in targeting it. Lastly, we discuss opportunities and future directions of this drug target space. Mycolacterium tuberculosis; energy metabolism; electron transport chain; oxidative phosphorylation; tuberculosis; drug discovery; bedaquiline; Q203 20  
DR-TB by targeting the mycobacterial F\({}_{1}\)F\({}_{0}\) ATP synthase [7]. This has been followed by the regulatory approvals of nitroimidazoles delamanid (Deltyba; DEL) and pretomanid (PA-824) [8; 9], with the demonstration of PA-824 killing non-replicating _M. tb_ by inhibition of the respiratory cytochromes through the release of nitric oxide (NO) [10]. Additionally, Telacebec (Q203), which is currently in Phase 2 clinical trials, targets the primary terminal oxidase cytochrome bcc-aa3 complex (Cyt-bcc-aa3) of _M. tb_[11; 12]. Altogether, this highlights the vulnerability of energy metabolism in this pathogen and the sensitivity of components of the OxPhos pathway to specific chemical inhibition. Despite the high degree of conservation of this pathway between prokaryotes and eukaryotes, the ability to specifically target mycobacterial components without affecting the human mitochondrial counterparts has alleviated safety concerns, opening up a new and attractive target space for drug discovery. From a biological viewpoint, this pathway is promising as a drug target space for several reasons. Whereas substrate-level phosphorylation can provide a sufficient amount of energy for replication in many bacteria, _M. tb_ is dependent on the more energetically-efficient OxPhos to sustain growth [13; 14; 15]. This is probably linked to the absence of a NADH-dependent lactate dehydrogenase in mycobacteria, which would limit efficient fermentation [16; 17]. During the OxPhos process, electrons are transferred from electron donors of central metabolism to oxygen through the electron transport chain (ETC). The energy released in this transfer is conserved by the proton-pumping components of the ETC, generating an electrochemical gradient in the form of a proton motive force (PMF). This stored energy is then mined through the ATP synthase as protons flow back down the gradient to yield ATP. Since a sustained PMF and ATP replenishment are essential even for the viability of non-replicating _M. tb_[18; 19; 20; 21], it is believed that inhibition of the OxPhos pathway is an effective strategy to eradicate non-replicating subpopulations, thereby shortening future treatment durations. Moreover, since drug efflux pumps are energy-dependent in actively transporting drugs out of the bacterial cell, perturbation of the PMF and ATP levels may interfere with their function as well [13]. It has been demonstrated that efflux pump activities play a significant role in drug susceptibility of _M. tb_[22; 23; 24; 25; 26; 27] and, therefore, perturbation of the OxPhos pathway may indirectly aid in overcoming issues of efflux-pump mediated drug resistance.