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.
Highlights
Tuberculosis (TB) continues to have a significant global burden by remaining one of the top ten killers worldwide and the leading cause of death due to a single infectious agent [1]
Beites et al further demonstrated that NDH-2 silencing studies of nuo, ndh, and ndhA performed by Vilcheze et al, established that individually, enzymes are jointly essential for growth in the presence of long-chain fatty acids, but are dispensable none of the NADH dehydrogenases are essential in vitro or in vivo [34]
To date, tackling the mycobacterial oxidative phosphorylation (OxPhos) pathway has been a prolific avenue in finding new inhibitors against M. tb, as well as other mycobacteria such as M. ulcerans
Summary
Tuberculosis (TB) continues to have a significant global burden by remaining one of the top ten killers worldwide and the leading cause of death due to a single infectious agent [1]. 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, perturbation of the OxPhos pathway may indirectly aid in overcoming issues of efflux-pump mediated drug resistance In light of these significant interests in targeting energy metabolism in mycobacteria, this review aims to (1) summarise key findings of the main components comprising the OxPhos pathway of M. tb, (2) provide an overview of validated inhibitors of this pathway which are either in the discovery stage, in clinical development, or have been approved, (3) discuss the potential of new regimens containing these inhibitors, (4) highlight possible concerns in targeting this pathway, and (5) discuss future opportunities and directions for drug development in this space. There is a proton-translocating type I tb possesses three membrane-bound
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