Abstract
Mycobacterium tuberculosis (Mtb) exhibits remarkable metabolic flexibility that enables it to survive a plethora of host environments during its life cycle. With the advent of bedaquiline for treatment of multidrug-resistant tuberculosis, oxidative phosphorylation has been validated as an important target and a vulnerable component of mycobacterial metabolism. Exploiting the dependence of Mtb on oxidative phosphorylation for energy production, several components of this pathway have been targeted for the development of new antimycobacterial agents. This includes targeting NADH dehydrogenase by phenothiazine derivatives, menaquinone biosynthesis by DG70 and other compounds, terminal oxidase by imidazopyridine amides and ATP synthase by diarylquinolines. Importantly, oxidative phosphorylation also plays a critical role in the survival of persisters. Thus, inhibitors of oxidative phosphorylation can synergize with frontline TB drugs to shorten the course of treatment. In this review, we discuss the oxidative phosphorylation pathway and development of its inhibitors in detail.
Highlights
Tuberculosis (TB) remains a leading cause of death worldwide, with an estimated 1.3 million mortalities in 2016
We have provided an overview of the machinery involved in oxidative phosphorylation and the development of inhibitors targeting the components of oxidative phosphorylation
We have primarily focused on NADH
Summary
Tuberculosis (TB) remains a leading cause of death worldwide, with an estimated 1.3 million mortalities in 2016. Treatment of MDR TB requires administration of a multitude of second-line TB drugs for 18–24 months; this leads to cure rates of 60–70%. These low cure rates could be further confounded by other factors, such as co-infections and poor nutrition Given these observations, new drugs with novel mechanisms of action are urgently required. Extensive research efforts have been made in this direction, and the U.S Food and Drug Administration has recently approved two new drugs These drugs are bedaquiline (BDQ), a diarylquinoline ATP synthase inhibitor, and delamanid, a nitro-dihydro-imidazooxazole derivative that inhibits mycolic acid biosynthesis. Accelerated approval of these drugs has raised hope for a new regimen that could improve the outcome of treatment and reduce daily dose burden. We have provided an overview of the machinery involved in oxidative phosphorylation and the development of inhibitors (listed in Table 1) targeting the components of oxidative phosphorylation
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