Title | Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Wong AI, Beites T, Planck KA, Fieweger RA, Eckartt KA, Li S, Poulton NC, VanderVen BC, Rhee KY, Schnappinger D, Ehrt S, Rock J |
Journal | Elife |
Volume | 12 |
Date Published | 2023 Feb 22 |
ISSN | 2050-084X |
Keywords | Cyclic AMP, Drug Resistance, Fatty Acids, Humans, Mycobacterium tuberculosis, Tuberculosis |
Abstract | 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. |
DOI | 10.7554/eLife.81177 |
Alternate Journal | Elife |
PubMed ID | 36810158 |
PubMed Central ID | PMC9995111 |
Grant List | U19 AI162584 / AI / NIAID NIH HHS / United States 1DP2AI144850-01 / AI / NIAID NIH HHS / United States P01AI143575 / NH / NIH HHS / United States P01 AI143575 / AI / NIAID NIH HHS / United States DP2 AI144850 / AI / NIAID NIH HHS / United States INV-004709 / GATES / Bill & Melinda Gates Foundation / United States R01130018 / NH / NIH HHS / United States U19AI162584 / NH / NIH HHS / United States |
Submitted by ljc4002 on August 21, 2025 - 1:42pm