2023
DOI: 10.7554/elife.81177
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Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. 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 lack… Show more

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Cited by 15 publications
(14 citation statements)
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“…Our results clearly suggest that in contrast to phoPR -KO, both WT-Rv0805 and WT-Rv0805M share a comparable expression profile of complex lipid biosynthesis genes as that of WT (Figure 4 - figure supplement 1B). These results suggest that both strains expressing WT- or the mutant PDEs share a similar cell-wall properties and are consistent with a recent study reporting no significant effect of cAMP dysregulation on mycobacterial cell wall structure/ permeability (Wong et al , 2022). Together, our findings facilitate an integrated view of our results suggesting that higher susceptibility of WT-Rv0805 to stress conditions, is most likely controlled by mycobacterial cAMP level.…”
Section: Resultssupporting
confidence: 92%
“…Our results clearly suggest that in contrast to phoPR -KO, both WT-Rv0805 and WT-Rv0805M share a comparable expression profile of complex lipid biosynthesis genes as that of WT (Figure 4 - figure supplement 1B). These results suggest that both strains expressing WT- or the mutant PDEs share a similar cell-wall properties and are consistent with a recent study reporting no significant effect of cAMP dysregulation on mycobacterial cell wall structure/ permeability (Wong et al , 2022). Together, our findings facilitate an integrated view of our results suggesting that higher susceptibility of WT-Rv0805 to stress conditions, is most likely controlled by mycobacterial cAMP level.…”
Section: Resultssupporting
confidence: 92%
“…Mycobacterial genomes encode a complex cAMP synthesizing, utilizing, and degrading machinery ( 3 , 9 , 40 ), emphasizing the diversity in how this ancient small molecule is deployed in regulating bacterial physiology. For example, changes in cAMP levels affect the utilization of long-chain fatty acids, an important carbon source for intracellular mycobacteria ( 10 ). Further, an increase in cAMP levels decreases cholesterol utilization ( 41 ).…”
Section: Discussionmentioning
confidence: 99%
“…It has now been well-established that cAMP levels are high in mycobacteria ( 2 , 3 ), and cAMP is also secreted to the extracellular milieu ( 2 , 3 , 4 ). As seen in many other pathogenic bacteria, M. tuberculosis utilizes cyclic AMP-mediated signaling to subvert the host ( 3 , 5 , 6 ), and a remarkably high number of adenylyl cyclases as well as cAMP effector proteins are encoded in its genome ( 3 , 7 , 8 , 9 , 10 ). However, fast-growing nonpathogenic members, such as Mycobacterium smegmatis , also harbor multiple adenylyl cyclases and cAMP-binding proteins ( 9 , 11 ).…”
mentioning
confidence: 99%
“…Consistent with our observation, Rv1339 encodes a second messenger signaling enzyme that modulates drug susceptibility and is undergoing positive selections in clinical isolates. 10,46,49 By identifying bacterial-intrinsic intermediate traits that link these mutations to the clinical phenotypes, we establish the plausibility that bacterial phenogenomic variation contributes to patient outcomes along with other factors with established associations with cavitary disease and treatment failure such as antibiotic adherence, comorbidities, drug resistance, and disease severity. 24,55,56 The relationship between decreased fitness in acetate + propionate, glycerol, and BDQ with the clinical and epidemiological outcomes is not immediately intuitive, as one might assume that increased fitness to stress would be a better predictor.…”
Section: Discussionmentioning
confidence: 99%
“…Rv1339, which has been implicated in modulating Mtb antibiotic susceptibility and is undergoing positive selection in TB patients globally was the only monogenic determinant associated with treatment failure (OR=5•34, CI=1•21-23•58, P=0•027), but not cavitary disease, suggesting disparate mechanisms may be accounting for these two distinct clinical outcomes associated with the L1.1.1.1 strains. 10,46,49 We performed Mantel-Haenszel analyses to ensure that the associations we identified with L1.1.1.1 and Rv1339 mutations are not explained by patient age or sex (S8 Table ).…”
Section: Mtb L1 Clade Is Associated With Poor Clinical Outcomes and I...mentioning
confidence: 99%