Metabolic principles of persistence and pathogenicity in Mycobacterium tuberculosis

Abstract

Metabolism was once relegated to the supply of energy and biosynthetic precursors, but it has now become clear that it is a specific mediator of nearly all physiological processes. In the context of microbial pathogenesis, metabolism has expanded outside its canonical role in bacterial replication. Among human pathogens, this expansion has emerged perhaps nowhere more visibly than for Mycobacterium tuberculosis, the causative agent of tuberculosis. Unlike most pathogens, M. tuberculosis has evolved within humans, which are both host and reservoir. This makes unrestrained replication and perpetual quiescence equally incompatible strategies for survival as a species. In this Review, we summarize recent work that illustrates the diversity of metabolic functions that not only enable M. tuberculosis to establish and maintain a state of chronic infection within the host but also facilitate its survival in the face of drug pressure and, ultimately, completion of its life cycle.

Figure 1. Enzymes required for growth and/or persistence of M. tuberculosis

Schematic representation of central carbon metabolism pathways and key enzymes in M. tuberculosis. Enzymatic steps dedicated to glycolysis are depicted in light blue, reversible steps of glycolysis/gluconeogenesis are depicted in pink, dedicated steps of gluconeogenesis are depicted in red, the TCA cycle is depicted in green, the glyoxylate shunt is depicted in orange, and the methylcitrate cycle is depicted in dark blue. Pathways of glycerol and glyerolphospholipid metabolism are depicted in grey. GK, glucokinase; GLPK, glycerol kinase; GPP, glycerol phosphate phosphatase; FBP, fructose bisphosphatase; FBA, fructose bisphosphate aldolase; TPI, triosephosphate isomerase; PK, pyruvate kinase; PDH, pyruvate dehydrogenase; KDH, ketoglutarate dehydrogenase; ICL, isocitrate lyase; SDH, succinate dehydrogenase; FUM, fumarase; MS, malate synthase; PEPCK, phosphoenolpyruvate caboxykinase.

Figure 2. Effects of metabolism beyond fulfilling nutritional demands on the physiology of M. tuberculosis

The pentose phosphate pathway supports peptidoglycan biosynthesis. Trehalose recycling from trehalose mycolates in the cell envelope facilitates exit from hypoxia and re-entry into active replication through the generation of glycolytic intermediates including phosphoenol pyruvate (PEP). The pyruvate dehydrogenase (PDH) complex and the α-ketoglutarate (KDH) complex share enzymes with the peroxynitrite reductase and peroxidase (PNR-P) complex and provide antioxidant defense. Isocitrate lyase (ICL) serves antioxidant functions and facilitates drug tolerance. The TCA metabolite succinate controls membrane potential.

Figure 3. Immunoreactive cell envelope lipids of M. tuberculosis

Trehalose dimycolate (TDM) activates Mincle on macrophages to stimulate proinflammatory cytokine secretion and granuloma formation. Mycolic acids confer acid fastness and are crucial for virulence. The mycolic acid chains are antigenic determinants for the conserved human germline encoded mycolyl lipid-reactive (GEM) T cell receptors (TCRs) and may modulate T cell responses. Phthiocerol dimycocerosate (PDIM) has been shown to contribute to virulence by multiple mechanisms, including by stimulating phagocytosis, protecting against nitric oxide (NO), promoting escape from the phagosome and inducing host cell death. Sulfolipids and sulfoglycolipids (SGLs) are immunomodulatory and required for virulence. SGLs can antagonize TLR2 and thereby interfere with recognition by the immune system.

Figure 4. Identification of a small-molecule allosteric inhibitor of tryptophan synthase (TrpAB) in M. tuberculosis

High-throughput screening identified compounds that inhibit the growth of against M. tuberculosis. Compounds with a low minimum inhibitory concentration (MIC) were used to select for resistant mutants. This suggested tryptophane synthase as target. The co-crystal structure shows that the inhibitor binds to TrpAB outside of the active site of the enzyme. Structural image adapted with permission from ref.