Abstract
Mycobacterium tuberculosis (Mtb) has evolved into a highly successful human pathogen. It deftly subverts the bactericidal mechanisms of alveolar macrophages, ultimately inducing granuloma formation and establishing long-term residence in the host. These hallmarks of Mtb infection are facilitated by the metabolic adaptation of the pathogen to its surrounding environment and the biosynthesis of molecules that mediate its interactions with host immune cells. The sulfate assimilation pathway of Mtb produces a number of sulfur-containing metabolites with important contributions to pathogenesis and survival. This pathway is regulated by diverse environmental cues and regulatory proteins that mediate sulfur transactions in the cell. Here, we discuss the transcriptional and biochemical mechanisms of sulfur metabolism regulation in Mtb and potential small molecule regulators of the sulfate assimilation pathway that are collectively poised to aid this intracellular pathogen in its expert manipulation of the host. From this global analysis, we have identified a subset of sulfur-metabolizing enzymes that are sensitive to multiple regulatory cues and may be strong candidates for therapeutic intervention.
Highlights
Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis in humans, infects roughly 2 billion people worldwide [1]
These cells form a protective barrier between the bacteria and surrounding tissue known as the granuloma [4,5]
The regulation of Mtb sulfur metabolism relies on the transcriptional response of sulfate assimilation enzymes to diverse environmental cues and regulatory proteins that influence flux through the sulfate assimilation pathway
Summary
Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis in humans, infects roughly 2 billion people worldwide [1]. The regulation of Mtb sulfur metabolism relies on the transcriptional response of sulfate assimilation enzymes to diverse environmental cues and regulatory proteins that influence flux through the sulfate assimilation pathway. PLoS Pathogens | www.plospathogens.org regulation of sulfur metabolism in other bacteria suggests similar mechanisms may modulate related transcriptional circuits in Mtb. Here, we review each of these regulatory elements in an effort to guide our understanding of how the sulfate assimilation pathway facilitates bacterial adaptation to the host.
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