Deciphering the role of the Mycobacterium tuberculosis exometabolome in mycobacterial virulence

ongoing

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), exhibits an intracellular lifestyle, thriving within host macrophages. This remarkable ability to evade macrophage-mediated killing and withstand the challenges posed by the host environment hinges largely on its exceptional capacity to adapt its metabolism in response to the diverse conditions encountered during infection. Despite progress, our comprehension of Mtb metabolic adjustments in these circumstances remains limited. Preliminary investigations conducted within the host laboratory have unveiled that Mtb releases a multitude of small, soluble molecules into its extracellular milieu when cultured in vitro. These metabolites potentially exert a substantial influence at the host-pathogen interface, subsequently shaping the delicate equilibrium established between the bacterium and its host throughout the course of infection. This proposal is centered on elucidating the role of Mtb exometabolome at host-pathogen interface, with the overarching objectives of (i) advancing our insight into Mtb metabolism and (ii) pinpointing potential novel virulence determinants that might be secreted by the microorganism. The primary phase involves the comprehensive identification and quantification of metabolites present in the bacterial culture medium. This will be achieved through untargeted metabolomics methodologies, primarily utilizing NMR and mass spectrometry. Subsequently, the metabolic pathways governing the biosynthesis and secretion of these metabolites will be characterized. This investigation seeks to unravel the underlying metabolic drivers facilitating the release of these compounds. The culmination of this project involves exploring the impact of a subset of significant metabolites on the physiology of infected macrophages, as well as their role in modulating the immune response. These assessments will encompass a spectrum of in vitro and in vivo strategies.