biostudies-literatureBrown KLCanadian Lung AssociationNIAID NIH HHSHHS | NIH | National Institute of Allergy and Infectious DiseasesGouvernement du Canada | Canadian Institutes of Health Researche0129422https://www.ebi.ac.uk/biostudies/studies/S-EPMC9872607biostudies-literatureUnknown67(1)Despite the deployment of combination tuberculosis (TB) chemotherapy, efforts to identify shorter, nonrelapsing treatments have resulted in limited success. Recent evidence indicates that GSK2556286 (GSK286), which acts via Rv1625c, a membrane-bound adenylyl cyclase in Mycobacterium tuberculosis, shortens treatment in rodents relative to standard of care drugs. Moreover, GSK286 can replace linezolid in the three-drug, Nix-TB regimen. Given its therapeutic potential, we sought to better understand the mechanism of action of GSK286. The compound blocked growth of <i>M. tuberculosis</i> in cholesterol media and increased intracellular cAMP levels ~50-fold. GSK286 did not inhibit growth of an <i>rv1625c</i> transposon mutant in cholesterol media and did not induce cyclic AMP (cAMP) production Antimicrobial agents and chemotherapyCyclic AMP-Mediated Inhibition of Cholesterol Catabolism in <i>Mycobacterium tuberculosis</i> by the Novel Drug Candidate GSK2556286.PMC9872607R01 AI130018AI130018PJT-159574AI119122R01 AI119122Wilburn KMMontague CREltis LDSanz OBrown KLBallell LGrigg JCBarros DPerez-Herran EVanderVen BCfalseCyclic AMP-Mediated Inhibition of Cholesterol Catabolism in <i>Mycobacterium tuberculosis</i> by the Novel Drug Candidate GSK2556286.Despite the deployment of combination tuberculosis (TB) chemotherapy, efforts to identify shorter, nonrelapsing treatments have resulted in limited success. Recent evidence indicates that GSK2556286 (GSK286), which acts via Rv1625c, a membrane-bound adenylyl cyclase in Mycobacterium tuberculosis, shortens treatment in rodents relative to standard of care drugs. Moreover, GSK286 can replace linezolid in the three-drug, Nix-TB regimen. Given its therapeutic potential, we sought to better understand the mechanism of action of GSK286. The compound blocked growth of <i>M. tuberculosis</i> in cholesterol media and increased intracellular cAMP levels ~50-fold. GSK286 did not inhibit growth of an <i>rv1625c</i> transposon mutant in cholesterol media and did not induce cyclic AMP (cAMP) production 2023-01-01T00:00:00Z2023 Jan2026-06-08T06:39:43.539Z2025-04-07T10:25:16.512ZS-EPMC98726073660233610.1128/aac.01294-22