Triazolopyrimidines target aerobic respiration in <i>Mycobacterium tuberculosis</i>

Shelton, Catherine; McNeil, Matthew B.; Flint, Lindsay; Russell, Dara; Berube, Bryan J.; Korkegian, Aaron; Ovechkina, Yulia; Parish, Tanya

doi:10.1101/2021.10.18.464924

Cited by 2 publications

(1 citation statement)

References 16 publications

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“…Finally, recent observations further suggest a link between cAMP and the electron transport chain. Isolation of spontaneous resistant mutants to a series of novel inhibitors of the QcrB subunit of the cytochrome bc1-aa3 oxidase repeatedly identify mutations in rv1339 (Chandrasekera et al, 2017;O'Malley et al, 2018;Shelton et al, 2021). How loss of rv1339 and elevated cAMP promotes resistance to QcrB inhibitors remains to be defined, but in principle could be achieved by elevated cAMP levels increasing electron transport chain activity, for example by increasing expression of the alternative terminal oxidase cytochrome bd (Ko and Oh, 2020).…”

Section: Discussionmentioning

confidence: 99%

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

Wong

Beites

Planck

et al. 2022

Preprint

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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 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 levels of cAMP result in 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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Section: Discussionmentioning

confidence: 99%

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

Wong

Beites

Planck

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

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

Wong

Beites

Planck

et al. 2023

eLife

View full text Add to dashboard Cite

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 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.

show abstract

Triazolopyrimidines target aerobic respiration in Mycobacterium tuberculosis

Cited by 2 publications

References 16 publications

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

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

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

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