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Mol Microbiol. 2017 Jul;105(2):294-308. doi: 10.1111/mmi.13701. Epub 2017 May 23.

Chemical activation of adenylyl cyclase Rv1625c inhibits growth of Mycobacterium tuberculosis on cholesterol and modulates intramacrophage signaling.

Author information

1
Department of Biomedical Sciences, School of Public Health, University at Albany, SUNY, Albany, NY, USA.
2
Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
3
Department of Chemistry, University at Albany, SUNY, Albany, NY, USA.
4
New York State Department of Health, Wadsworth Center, Albany, NY, USA.
5
Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.

Abstract

Mycobacterium tuberculosis (Mtb) uses a complex 3', 5'-cyclic AMP (cAMP) signaling network to sense and respond to changing environments encountered during infection, so perturbation of cAMP signaling might be leveraged to disrupt Mtb pathogenesis. However, understanding of cAMP signaling pathways is hindered by the presence of at least 15 distinct adenylyl cyclases (ACs). Recently, the small molecule V-58 was shown to inhibit Mtb replication within macrophages and stimulate cAMP production in Mtb. Here we determined that V-58 rapidly and directly activates Mtb AC Rv1625c to produce high levels of cAMP regardless of the bacterial environment or growth medium. Metabolic inhibition by V-58 was carbon source dependent in Mtb and did not occur in Mycobacterium smegmatis, suggesting that V-58-mediated growth inhibition is due to interference with specific Mtb metabolic pathways rather than a generalized cAMP toxicity. Chemical stimulation of cAMP production by Mtb within macrophages also caused down regulation of TNF-α production by the macrophages, indicating a complex role for cAMP in Mtb pathogenesis. Together these studies describe a novel approach for targeted stimulation of cAMP production in Mtb, and provide new insights into the myriad roles of cAMP signaling in Mtb, particularly during Mtb's interactions with macrophages.

PMID:
28464471
PMCID:
PMC5499149
DOI:
10.1111/mmi.13701
[Indexed for MEDLINE]
Free PMC Article

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