ArticlePLoS pathogens2022
Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis.
Article in PLoS pathogens, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 30 citations in OpenAlex.
- An adenylyl cyclase switch reroutes carbon from growth to virulence lipids inbioRxiv : the preprint server for biology · 2026Article
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- Integrating chemical, genetic, and feasibility assessments for anti-tubercular target validation.EMBO molecular medicine · 2026Review
- Phosphoglucomutase A-mediated metabolic adaptation is essential for antibiotic and disease persistence inmSystems · 2025Article
- Revolutionizing tuberculosis treatment: Breakthroughs, challenges, and hope on the horizon.Acta pharmaceutica Sinica. B · 2025Review
- Activation of nuclear receptors correlates with tuberculosis severity and is a target for host-directed therapy.Frontiers in cellular and infection microbiology · 2025Article
- A Review of Antibacterial Candidates with New Modes of Action.ACS infectious diseases · 2024Review
- Exploiting cAMP signaling in Mycobacterium tuberculosis for drug discovery.Trends in microbiology · 2024Review
- Article
- Mycobacterial phosphodiesterase Rv0805 is a virulence determinant and its cyclic nucleotide hydrolytic activity is required for propionate detoxification.Molecular microbiology · 2023Article
- Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism ineLife · 2023Article
- Cyclic AMP-Mediated Inhibition of Cholesterol Catabolism inAntimicrobial agents and chemotherapy · 2023Article
- Iron limitation in M. tuberculosis has broad impact on central carbon metabolism.Communications biology · 2022Article
- GSK2556286 Is a Novel Antitubercular Drug Candidate EffectiveAntimicrobial agents and chemotherapy · 2022Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3', 5'-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required during cholesterol metabolism. Finally, the pharmacokinetic properties of Rv1625c agonists have been optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies.
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Registered trials
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