Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis.

Autor:	Wilburn KM; Microbiology & Immunology, Cornell University, Ithaca, New York, United States of America., Montague CR; Microbiology & Immunology, Cornell University, Ithaca, New York, United States of America., Qin B; Calibr, a division of The Scripps Research Institute, San Diego, California, United States of America., Woods AK; Calibr, a division of The Scripps Research Institute, San Diego, California, United States of America., Love MS; Calibr, a division of The Scripps Research Institute, San Diego, California, United States of America., McNamara CW; Calibr, a division of The Scripps Research Institute, San Diego, California, United States of America., Schultz PG; Calibr, a division of The Scripps Research Institute, San Diego, California, United States of America., Southard TL; Biomedical Sciences, Cornell University, Ithaca, New York, United States of America., Huang L; Microbiology & Immunology, Cornell University, Ithaca, New York, United States of America., Petrassi HM; Calibr, a division of The Scripps Research Institute, San Diego, California, United States of America., VanderVen BC; Microbiology & Immunology, Cornell University, Ithaca, New York, United States of America.
Jazyk:	angličtina
Zdroj:	PLoS pathogens [PLoS Pathog] 2022 Feb 08; Vol. 18 (2), pp. e1009862. Date of Electronic Publication: 2022 Feb 08 (Print Publication: 2022).
DOI:	10.1371/journal.ppat.1009862
Abstrakt:	There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3', 5'-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required during cholesterol metabolism. Finally, the pharmacokinetic properties of Rv1625c agonists have been optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies. Competing Interests: The authors have declared that no competing interests exist.
Databáze:	MEDLINE
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