Editor's evaluation: Cyclic AMP is a critical mediator of intrinsic drug resistance and fatty acid metabolism in M. tuberculosis

Résumé

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. Editor's evaluationBacteria living in stressful and fluctuating environments need to respond to changing conditions, and many species, including Mycobacterium tuberculosis, the causative agent of tuberculosis, use cyclic AMP (cAMP) as a secondary messenger to sense and respond to specific stimuli.What distinguishes M. tuberculosis, is that its genome encodes at least 15 adenylate cyclases, enzymes that synthesize cAMP from ATP.Using state-of-the-art methods in this important study, the authors characterized one specific adenylate cyclase, Rv3645, and convincingly demonstrate that it is the most significant contributor to cAMP levels, in addition to mediating fatty acid metabolism and antibiotic resistance.This manuscript will be of broad interest to readers in the field of tuberculosis drug discovery and bacterial metabolism.

Citer ce document

Accès au document

Ce document est hébergé sur son dépôt institutionnel d'origine.

Auteur(s)

Statistiques

Consultations : 1

Téléchargements : 0