Novel Inhibitors of Cholesterol Degradation in Reveal How the Bacterium’s Metabolism Is Constrained by the Intracellular Environment

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Human beings are the sole ecological niche for M. tuberculosis (Mtb), and it is estimated that 1.8 billion people are currently infected with Mtb. An important aspect of this infection is Mtb’s ability to maintain infection by replicating within macrophages. Within macrophages, Mtb exploits a specialized set of metabolic pathways to utilize host-derived nutrients, such as fatty acids and/or cholesterol, for energy production. Many details regarding Mtb metabolism during infection remain unknown. Here we took a chemical approach to identify small molecule probes, which target Mtb metabolism during infection in macrophages. We found that many of the small molecule inhibitors that we identified require cholesterol for activity. Here we report a novel chemical rescue approach to identify the metabolic targets of three novel inhibitors, and discovered that cAMP signaling is linked to cholesterol utilization in Mtb. Together, these data demonstrate that cholesterol exerts a dominant effect on Mtb metabolism within macrophages. Additionally, the novel inhibitors identified in this study will facilitate evaluation of cholesterol metabolism as a target for chemotherapeutic intervention.

Vyšlo v časopise: Novel Inhibitors of Cholesterol Degradation in Reveal How the Bacterium’s Metabolism Is Constrained by the Intracellular Environment. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004679
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004679

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