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

TitleCyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis.
Publication TypeJournal Article
Year of Publication2023
AuthorsWong AI, Beites T, Planck KA, Fieweger RA, Eckartt KA, Li S, Poulton NC, VanderVen BC, Rhee KY, Schnappinger D, Ehrt S, Rock J
JournalElife
Volume12
Date Published2023 Feb 22
ISSN2050-084X
KeywordsCyclic 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.

DOI10.7554/eLife.81177
Alternate JournalElife
PubMed ID36810158
PubMed Central IDPMC9995111
Grant ListU19 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

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