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Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs
- J. Fraser Glickman
- Shumin Tan
- Joel Freundlich
Date created: 2021-05-27 01:24 PM | Last Updated: 2021-07-11 03:19 PM
Identifier: DOI 10.17605/OSF.IO/HEGD3
Category: Data
Description: Sensing and response to environmental cues, such as pH and chloride (Cl-), is critical in enabling Mycobacterium tuberculosis (Mtb) colonization of its host. Utilizing a fluorescent reporter Mtb strain in a chemical screen, we have identified compounds that dysregulate Mtb response to high Cl- levels, with a subset of the hits also inhibiting Mtb growth in host macrophages. Structure-activity relationship studies on the hit compound “C6” demonstrated a correlation between compound perturbation of Mtb Cl- response and inhibition of bacterial growth in macrophages. C6 accumulated in both bacterial and host cells, and inhibited Mtb growth in cholesterol media, but not in rich media. Strikingly, oral administration of C6 was able to inhibit Mtb growth in vivo in a C3HeB/FeJ murine infection model. Our work illustrates how Mtb response to environmental cues can intersect with its metabolism, and be exploited in antitubercular drug discovery.
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