Abstract
Despite decades of dedicated research, there remains a dire need for new drugs against tuberculosis (TB). Current therapies are generations old and problematic. Resistance to these existing therapies results in an ever-increasing burden of patients with disease that is difficult or impossible to treat. Novel chemical entities with new mechanisms of action are therefore earnestly required. The biosynthesis of coenzyme A (CoA) has long been known to be essential in Mycobacterium tuberculosis (Mtb), the causative agent of TB. The pathway has been genetically validated by seminal studies in vitro and in vivo. In Mtb, the CoA biosynthetic pathway is comprised of nine enzymes: four to synthesize pantothenate (Pan) from l-aspartate and α-ketoisovalerate; five to synthesize CoA from Pan and pantetheine (PantSH). This review gathers literature reports on the structure/mechanism, inhibitors, and vulnerability of each enzyme in the CoA pathway. In addition to traditional inhibition of a single enzyme, the CoA pathway offers an antimetabolite strategy as a promising alternative. In this review, we provide our assessment of what appear to be the best targets, and, thus, which CoA pathway enzymes present the best opportunities for antitubercular drug discovery moving forward.
Highlights
Despite a dramatic increase in innovative research over the last two decades, there remains a clear and pressing need for new antitubercular drugs
There is considerable support in the form of genetic and in silico validation studies of several of the pathway enzymes being high confidence drug targets, and small molecule inhibitors with nanomolar potency has been developed in the case of some enzymes, very few of these compounds show whole cell activity, with none being active in vivo
MtPanD and Mtb CoaBC (MtCoaBC) currently appear to be the most likely targets to yield positive results; the former based on the recent findings that link the activity of the well-known antiTB agent PZA (52) to inhibition and/or degradation of MtPanD, and the latter based on the bacteriocidal effects and in vivo efficacy of targeted depletion of MtCoaBC
Summary
Despite a dramatic increase in innovative research over the last two decades, there remains a clear and pressing need for new antitubercular drugs. 1.4 million people continue to die of tuberculosis (TB), and the rates of drug resistant disease are on the rise “WHO MDR-TB Factsheet 2018” 2019; (World Health Organization, 2020). Caused by Mycobacterium tuberculosis (Mtb), drug-susceptible TB is typically treated using a cocktail of drugs, including rifampicin and isoniazid (World Health Organization, 2017). Mtb strains resistant to one or both of these two key TB drugs are exceedingly difficult to treat. As resistance to current drugs is a clear issue, compounds with mechanisms of action distinct from those of existing therapies are desperately needed.
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