**Caroline Shi-Yan Foo 1, Kevin Pethe 2,\* and Andréanne Lupien 3,4,\***


Received: 29 February 2020; Accepted: 24 March 2020; Published: 29 March 2020

**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®), 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.

**Keywords:** *Mycobacterium tuberculosis*; energy metabolism; electron transport chain; oxidative phosphorylation; tuberculosis; drug discovery; bedaquiline; Q203
