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Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis

Cyclic AMP (cAMP) is a ubiquitous second messenger that transduces signals from cellular receptors to downstream effectors. Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, devotes a considerable amount of coding capacity to produce, sense, and degrade cAMP. Despite this fact...

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Autores principales: Wong, Andrew I, Beites, Tiago, Planck, Kyle A, Fieweger, Rachael A, Eckartt, Kathryn A, Li, Shuqi, Poulton, Nicholas C, VanderVen, Brian C, Rhee, Kyu Y, Schnappinger, Dirk, Ehrt, Sabine, Rock, Jeremy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995111/
https://www.ncbi.nlm.nih.gov/pubmed/36810158
http://dx.doi.org/10.7554/eLife.81177
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author Wong, Andrew I
Beites, Tiago
Planck, Kyle A
Fieweger, Rachael A
Eckartt, Kathryn A
Li, Shuqi
Poulton, Nicholas C
VanderVen, Brian C
Rhee, Kyu Y
Schnappinger, Dirk
Ehrt, Sabine
Rock, Jeremy
author_facet Wong, Andrew I
Beites, Tiago
Planck, Kyle A
Fieweger, Rachael A
Eckartt, Kathryn A
Li, Shuqi
Poulton, Nicholas C
VanderVen, Brian C
Rhee, Kyu Y
Schnappinger, Dirk
Ehrt, Sabine
Rock, Jeremy
author_sort Wong, Andrew I
collection PubMed
description Cyclic AMP (cAMP) is a ubiquitous second messenger that transduces signals from cellular receptors to downstream effectors. Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, devotes a considerable amount of coding capacity to produce, sense, and degrade cAMP. Despite this fact, our understanding of how cAMP regulates Mtb physiology remains limited. Here, we took a genetic approach to investigate the function of the sole essential adenylate cyclase in Mtb H37Rv, Rv3645. We found that a lack of rv3645 resulted in increased sensitivity to numerous antibiotics by a mechanism independent of substantial increases in envelope permeability. We made the unexpected observation that rv3645 is conditionally essential for Mtb growth only in the presence of long-chain fatty acids, a host-relevant carbon source. A suppressor screen further identified mutations in the atypical cAMP phosphodiesterase rv1339 that suppress both fatty acid and drug sensitivity phenotypes in strains lacking rv3645. Using mass spectrometry, we found that Rv3645 is the dominant source of cAMP under standard laboratory growth conditions, that cAMP production is the essential function of Rv3645 in the presence of long-chain fatty acids, and that reduced cAMP levels result in increased long-chain fatty acid uptake and metabolism and increased antibiotic susceptibility. Our work defines rv3645 and cAMP as central mediators of intrinsic multidrug resistance and fatty acid metabolism in Mtb and highlights the potential utility of small molecule modulators of cAMP signaling.
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spelling pubmed-99951112023-03-09 Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis Wong, Andrew I Beites, Tiago Planck, Kyle A Fieweger, Rachael A Eckartt, Kathryn A Li, Shuqi Poulton, Nicholas C VanderVen, Brian C Rhee, Kyu Y Schnappinger, Dirk Ehrt, Sabine Rock, Jeremy eLife Microbiology and Infectious Disease Cyclic AMP (cAMP) is a ubiquitous second messenger that transduces signals from cellular receptors to downstream effectors. Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, devotes a considerable amount of coding capacity to produce, sense, and degrade cAMP. Despite this fact, our understanding of how cAMP regulates Mtb physiology remains limited. Here, we took a genetic approach to investigate the function of the sole essential adenylate cyclase in Mtb H37Rv, Rv3645. We found that a lack of rv3645 resulted in increased sensitivity to numerous antibiotics by a mechanism independent of substantial increases in envelope permeability. We made the unexpected observation that rv3645 is conditionally essential for Mtb growth only in the presence of long-chain fatty acids, a host-relevant carbon source. A suppressor screen further identified mutations in the atypical cAMP phosphodiesterase rv1339 that suppress both fatty acid and drug sensitivity phenotypes in strains lacking rv3645. Using mass spectrometry, we found that Rv3645 is the dominant source of cAMP under standard laboratory growth conditions, that cAMP production is the essential function of Rv3645 in the presence of long-chain fatty acids, and that reduced cAMP levels result in increased long-chain fatty acid uptake and metabolism and increased antibiotic susceptibility. Our work defines rv3645 and cAMP as central mediators of intrinsic multidrug resistance and fatty acid metabolism in Mtb and highlights the potential utility of small molecule modulators of cAMP signaling. eLife Sciences Publications, Ltd 2023-02-22 /pmc/articles/PMC9995111/ /pubmed/36810158 http://dx.doi.org/10.7554/eLife.81177 Text en © 2023, Wong et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Microbiology and Infectious Disease
Wong, Andrew I
Beites, Tiago
Planck, Kyle A
Fieweger, Rachael A
Eckartt, Kathryn A
Li, Shuqi
Poulton, Nicholas C
VanderVen, Brian C
Rhee, Kyu Y
Schnappinger, Dirk
Ehrt, Sabine
Rock, Jeremy
Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis
title Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis
title_full Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis
title_fullStr Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis
title_full_unstemmed Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis
title_short Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis
title_sort cyclic amp is a critical mediator of intrinsic drug resistance and fatty acid metabolism in m. tuberculosis
topic Microbiology and Infectious Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995111/
https://www.ncbi.nlm.nih.gov/pubmed/36810158
http://dx.doi.org/10.7554/eLife.81177
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