Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs.
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- level...
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2021
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oai:doaj.org-article:e8e92b4c6c2a4557821d17bd956725722021-12-02T19:54:21ZTargeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs.1544-91731545-788510.1371/journal.pbio.3001355https://doaj.org/article/e8e92b4c6c2a4557821d17bd956725722021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.3001355https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Sensing 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," or 2-(4-((2-(ethylthio)pyrimidin-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole, 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. Subsequent examination of the Cl- response of Mtb revealed an intriguing link with bacterial growth in cholesterol, with increased transcription of several Cl--responsive genes in the simultaneous presence of cholesterol and high external Cl- concentration, versus transcript levels observed during exposure to high external Cl- concentration alone. 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.Richard C LavinCalvin JohnsonYong-Mo AhnKyle M KremillerMatthew SherwoodJimmy S PatelYan PanRiccardo RussoNathan J MacGilvaryDavid GiacaloneYuzo L KevorkianMatthew D ZimmermanJ Fraser GlickmanJoel S FreundlichShumin TanPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 7, p e3001355 (2021) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Biology (General) QH301-705.5 |
| spellingShingle |
Biology (General) QH301-705.5 Richard C Lavin Calvin Johnson Yong-Mo Ahn Kyle M Kremiller Matthew Sherwood Jimmy S Patel Yan Pan Riccardo Russo Nathan J MacGilvary David Giacalone Yuzo L Kevorkian Matthew D Zimmerman J Fraser Glickman Joel S Freundlich Shumin Tan Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs. |
| 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," or 2-(4-((2-(ethylthio)pyrimidin-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole, 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. Subsequent examination of the Cl- response of Mtb revealed an intriguing link with bacterial growth in cholesterol, with increased transcription of several Cl--responsive genes in the simultaneous presence of cholesterol and high external Cl- concentration, versus transcript levels observed during exposure to high external Cl- concentration alone. 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. |
| format |
article |
| author |
Richard C Lavin Calvin Johnson Yong-Mo Ahn Kyle M Kremiller Matthew Sherwood Jimmy S Patel Yan Pan Riccardo Russo Nathan J MacGilvary David Giacalone Yuzo L Kevorkian Matthew D Zimmerman J Fraser Glickman Joel S Freundlich Shumin Tan |
| author_facet |
Richard C Lavin Calvin Johnson Yong-Mo Ahn Kyle M Kremiller Matthew Sherwood Jimmy S Patel Yan Pan Riccardo Russo Nathan J MacGilvary David Giacalone Yuzo L Kevorkian Matthew D Zimmerman J Fraser Glickman Joel S Freundlich Shumin Tan |
| author_sort |
Richard C Lavin |
| title |
Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs. |
| title_short |
Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs. |
| title_full |
Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs. |
| title_fullStr |
Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs. |
| title_full_unstemmed |
Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs. |
| title_sort |
targeting mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/e8e92b4c6c2a4557821d17bd95672572 |
| work_keys_str_mv |
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1718375935671009280 |