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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/81177 |
| _version_ | 1811158106542964736 |
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| author | Andrew I Wong Tiago Beites Kyle A Planck Rachael A Fieweger Kathryn A Eckartt Shuqi Li Nicholas C Poulton Brian C VanderVen Kyu Y Rhee Dirk Schnappinger Sabine Ehrt Jeremy Rock |
| author_facet | Andrew I Wong Tiago Beites Kyle A Planck Rachael A Fieweger Kathryn A Eckartt Shuqi Li Nicholas C Poulton Brian C VanderVen Kyu Y Rhee Dirk Schnappinger Sabine Ehrt Jeremy Rock |
| author_sort | Andrew I Wong |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T05:17:39Z |
| format | Article |
| id | doaj.art-fe201b0981a543b4b8b62123b421ec24 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-10T05:17:39Z |
| publishDate | 2023-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-fe201b0981a543b4b8b62123b421ec242023-03-08T16:34:27ZengeLife Sciences Publications LtdeLife2050-084X2023-02-011210.7554/eLife.81177Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosisAndrew I Wong0Tiago Beites1Kyle A Planck2Rachael A Fieweger3Kathryn A Eckartt4Shuqi Li5https://orcid.org/0000-0002-8133-6838Nicholas C Poulton6Brian C VanderVen7https://orcid.org/0000-0003-3655-4390Kyu Y Rhee8Dirk Schnappinger9Sabine Ehrt10https://orcid.org/0000-0002-7951-2310Jeremy Rock11https://orcid.org/0000-0002-9310-951XLaboratory of Host-Pathogen Biology, The Rockefeller University, New York, United StatesDepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, United StatesDepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, United States; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, United StatesDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, United StatesLaboratory of Host-Pathogen Biology, The Rockefeller University, New York, United StatesLaboratory of Host-Pathogen Biology, The Rockefeller University, New York, United StatesLaboratory of Host-Pathogen Biology, The Rockefeller University, New York, United StatesDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, United StatesDepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, United States; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, United StatesDepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, United StatesDepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, United StatesLaboratory of Host-Pathogen Biology, The Rockefeller University, New York, United StatesCyclic 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.https://elifesciences.org/articles/81177M. tuberculosiscAMPantibiotic resistancemetabolismfatty acids |
| spellingShingle | Andrew I Wong Tiago Beites Kyle A Planck Rachael A Fieweger Kathryn A Eckartt Shuqi Li Nicholas C Poulton Brian C VanderVen Kyu Y Rhee Dirk Schnappinger Sabine Ehrt Jeremy Rock Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis eLife M. tuberculosis cAMP antibiotic resistance metabolism fatty acids |
| 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 | M. tuberculosis cAMP antibiotic resistance metabolism fatty acids |
| url | https://elifesciences.org/articles/81177 |
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