Two for the price of one: Attacking the energetic-metabolic hub of mycobacteria to produce new chemotherapeutic agents.

TitleTwo for the price of one: Attacking the energetic-metabolic hub of mycobacteria to produce new chemotherapeutic agents.
Publication TypeJournal Article
Year of Publication2020
AuthorsHards K, Adolph C, Harold LK, McNeil MB, Cheung C-Y, Jinich A, Rhee KY, Cook GM
JournalProg Biophys Mol Biol
Volume152
Pagination35-44
Date Published2020 05
ISSN1873-1732
KeywordsAntitubercular Agents, Benzoquinones, Citric Acid Cycle, Drug Discovery, Humans, Malates, Mycobacterium tuberculosis, NAD(P)H Dehydrogenase (Quinone), Oxidation-Reduction, Protein Binding, Succinate Dehydrogenase, Succinic Acid, Tuberculosis
Abstract

Cellular bioenergetics is an area showing promise for the development of new antimicrobials, antimalarials and cancer therapy. Enzymes involved in central carbon metabolism and energy generation are essential mediators of bacterial physiology, persistence and pathogenicity, lending themselves natural interest for drug discovery. In particular, succinate and malate are two major focal points in both the central carbon metabolism and the respiratory chain of Mycobacterium tuberculosis. Both serve as direct links between the citric acid cycle and the respiratory chain due to the quinone-linked reactions of succinate dehydrogenase, fumarate reductase and malate:quinone oxidoreductase. Inhibitors against these enzymes therefore hold the promise of disrupting two distinct, but essential, cellular processes at the same time. In this review, we discuss the roles and unique adaptations of these enzymes and critically evaluate the role that future inhibitors of these complexes could play in the bioenergetics target space.

DOI10.1016/j.pbiomolbio.2019.11.003
Alternate JournalProg Biophys Mol Biol
PubMed ID31733221