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

Simple item page
dc.contributor.authorWilburn, Kaley M.en
dc.contributor.authorMontague, Christine R.en
dc.contributor.authorQin, Boen
dc.contributor.authorWoods, Ashley K.en
dc.contributor.authorLove, Melissa S.en
dc.contributor.authorMcNamara, Case W.en
dc.contributor.authorSchultz, Peter G.en
dc.contributor.authorSouthard, Teresa L.en
dc.contributor.authorHuang, Luen
dc.contributor.authorPetrassi, H. Michaelen
dc.contributor.authorVanderVen, Brian C.en
dc.contributor.editorSassetti, Christopher M.en
dc.date.accessioned2023-02-17T19:56:35Zen
dc.date.available2023-02-17T19:56:35Zen
dc.date.issued2022-02-01en
dc.date.updated2023-02-13T20:36:56Zen
dc.description.abstractThere 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.en
dc.description.versionPublished versionen
dc.format.extent29 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN e1009862 (Article number)en
dc.identifier.doihttps://doi.org/10.1371/journal.ppat.1009862en
dc.identifier.eissn1553-7374en
dc.identifier.issn1553-7366en
dc.identifier.issue2en
dc.identifier.orcidSouthard, Teresa [0000-0001-8388-7951]en
dc.identifier.otherPPATHOGENS-D-21-01580 (PII)en
dc.identifier.pmid35134095en
dc.identifier.urihttp://hdl.handle.net/10919/113855en
dc.identifier.volume18en
dc.language.isoenen
dc.publisherPLOSen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000752832600001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectMicrobiologyen
dc.subjectParasitologyen
dc.subjectVirologyen
dc.subjectADENYLYL CYCLASESen
dc.subjectFATTY-ACIDen
dc.subjectMICEen
dc.subjectIMMUNOMETABOLISMen
dc.subjectPATHOLOGYen
dc.subjectREQUIRESen
dc.subjectRV1625Cen
dc.subjectFAMILYen
dc.subjectTuberculosisen
dc.subjectRare Diseasesen
dc.subjectInfectious Diseasesen
dc.subject2.2 Factors relating to the physical environmenten
dc.subject2.1 Biological and endogenous factorsen
dc.subject2 Aetiologyen
dc.subjectInfectionen
dc.subject3 Good Health and Well Beingen
dc.subject.meshAnimalsen
dc.subject.meshMice, Inbred BALB Cen
dc.subject.meshMycobacterium tuberculosisen
dc.subject.meshCholesterolen
dc.subject.meshBacterial Proteinsen
dc.subject.meshCyclic AMPen
dc.subject.meshSignal Transductionen
dc.subject.meshTranscriptional Activationen
dc.subject.meshAdenylyl Cyclasesen
dc.titlePharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosisen
dc.title.serialPLOS Pathogensen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2022-01-18en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/CVM T&R Facultyen

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Pharmacological and genetic.pdf
Size:
3.24 MB
Format:
Adobe Portable Document Format
Description:
Published version
Download

Collections

All Faculty Deposits
Scholarly Works, Biomedical Sciences and Pathobiology