ArticlePLoS pathogens2015
Novel inhibitors of cholesterol degradation in Mycobacterium tuberculosis reveal how the bacterium's metabolism is constrained by the intracellular environment.
Article in PLoS pathogens, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 158 papers.
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158 citing papers in PubMed, 268 citations in OpenAlex.
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- Fragment-Based Development of Small Molecule Inhibitors TargetingJournal of medicinal chemistry · 2025Article
- How macrophage heterogeneity affects tuberculosis disease and therapy.Nature reviews. Immunology · 2025Review
- Differential expression of genes associated with lipid import, β-oxidation and lactate oxidation induced byJournal of medical microbiology · 2025Article
- Metabolic pathway analysis of the methylcitrate cycle in bacteria and fungi identifies methylcitrate synthase as an antiinfective drug target.microLife · 2025Article
- Activation of nuclear receptors correlates with tuberculosis severity and is a target for host-directed therapy.Frontiers in cellular and infection microbiology · 2025Article
- TowardMicroorganisms · 2024Review
- A Review of Antibacterial Candidates with New Modes of Action.ACS infectious diseases · 2024Review
- Loss of glycerol catabolism confers carbon-source-dependent artemisinin resistance inAntimicrobial agents and chemotherapy · 2024Article
- Exploiting cAMP signaling in Mycobacterium tuberculosis for drug discovery.Trends in microbiology · 2024Review
98 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Mycobacterium tuberculosis (Mtb) relies on a specialized set of metabolic pathways to support growth in macrophages. By conducting an extensive, unbiased chemical screen to identify small molecules that inhibit Mtb metabolism within macrophages, we identified a significant number of novel compounds that limit Mtb growth in macrophages and in medium containing cholesterol as the principle carbon source. Based on this observation, we developed a chemical-rescue strategy to identify compounds that target metabolic enzymes involved in cholesterol metabolism. This approach identified two compounds that inhibit the HsaAB enzyme complex, which is required for complete degradation of the cholesterol A/B rings. The strategy also identified an inhibitor of PrpC, the 2-methylcitrate synthase, which is required for assimilation of cholesterol-derived propionyl-CoA into the TCA cycle. These chemical probes represent new classes of inhibitors with novel modes of action, and target metabolic pathways required to support growth of Mtb in its host cell. The screen also revealed a structurally-diverse set of compounds that target additional stage(s) of cholesterol utilization. Mutants resistant to this class of compounds are defective in the bacterial adenylate cyclase Rv1625/Cya. These data implicate cyclic-AMP (cAMP) in regulating cholesterol utilization in Mtb, and are consistent with published reports indicating that propionate metabolism is regulated by cAMP levels. Intriguingly, reversal of the cholesterol-dependent growth inhibition caused by this subset of compounds could be achieved by supplementing the media with acetate, but not with glucose, indicating that Mtb is subject to a unique form of metabolic constraint induced by the presence of cholesterol.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.