Acid Resistance in<i>Mycobacterium tuberculosis</i>

Vandal, Omar; Nathan, Carl; Ehrt, Sabine

doi:10.1128/jb.00305-09

Cited by 215 publications

(203 citation statements)

References 102 publications

(125 reference statements)

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“…C57BL/6 mice and IFNγ −/− mice on a C57BL/ 6 genetic background (Jackson Laboratory) were infected with Mtb by aerosol as described (37). When indicated, mice received doxycyclinecontaining mouse chow (2,000 ppm; Research Diets).…”

Section: Methodsmentioning

confidence: 99%

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Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection

Marrero¹,

Rhee

Schnappinger³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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304

315

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Metabolic adaptation to the host niche is a defining feature of the pathogenicity of Mycobacterium tuberculosis (Mtb). In vitro, Mtb is able to grow on a variety of carbon sources, but mounting evidence has implicated fatty acids as the major source of carbon and energy for Mtb during infection. When bacterial metabolism is primarily fueled by fatty acids, biosynthesis of sugars from intermediates of the tricarboxylic acid cycle is essential for growth. The role of gluconeogenesis in the pathogenesis of Mtb however remains unaddressed. Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the first committed step of gluconeogenesis. We applied genetic analyses and 13 C carbon tracing to confirm that PEPCK is essential for growth of Mtb on fatty acids and catalyzes carbon flow from tricarboxylic acid cycle-derived metabolites to gluconeogenic intermediates. We further show that PEPCK is required for growth of Mtb in isolated bone marrow-derived murine macrophages and in mice. Importantly, Mtb lacking PEPCK not only failed to replicate in mouse lungs but also failed to survive, and PEPCK depletion during the chronic phase of infection resulted in mycobacterial clearance. Mtb thus relies on gluconeogenesis throughout the infection. PEPCK depletion also attenuated Mtb in IFNγ-deficient mice, suggesting that this enzyme represents an attractive target for chemotherapy.carbon metabolism | gluconeogenesis | metabolomics | microbial pathogenesis | phosphoenolpyruvate carboxykinase

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Section: Methodsmentioning

confidence: 99%

“…Bacterial numbers were determined by plating homogenized organs for CFU. Bone marrow-derived mouse macrophages were isolated and infected with Mtb as described (37). The Institutional Animal Care and Use Committee of Weill Cornell Medical College approved murine experimental procedures.…”

Section: Methodsmentioning

confidence: 99%

Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection

Marrero¹,

Rhee

Schnappinger³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

304

315

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“…These secondary effects include the inhibition of enzymes involved in branched chain amino acid turnover, and those of the pyruvate dehydrogenase complex and electron transport chain and, ultimately, result in a cellular acidosis (9)(10)(11)(12). Membrane potential and cytosolic pH homeostasis are essential for the survival of all cells and potentially more so for those residing in acidic niches, including the phagosomes of immune-activated macrophages (13,14). Given the selective protection afforded by VB 12 against fatty acid-induced killing (Fig.…”

Section: -F)mentioning

confidence: 99%

Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids

Eoh

Rhee

2014

Proc. Natl. Acad. Sci. U.S.A.

144

177

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Few mutations attenuate Mycobacterium tuberculosis (Mtb) more profoundly than deletion of its isocitrate lyases (ICLs). However, the basis for this attenuation remains incompletely defined. Mtb's ICLs are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids. Here, we report that Mtb's ICLs are essential for survival on both acetate and propionate because of its methylisocitrate lyase (MCL) activity. Lack of MCL activity converts Mtb's methylcitrate cycle into a "dead end" pathway that sequesters tricarboxylic acid (TCA) cycle intermediates into methylcitrate cycle intermediates, depletes gluconeogenic precursors, and results in defects of membrane potential and intrabacterial pH. Activation of an alternative vitamin B 12 -dependent pathway of propionate metabolism led to selective corrections of TCA cycle activity, membrane potential, and intrabacterial pH that specifically restored survival, but not growth, of ICL-deficient Mtb metabolizing acetate or propionate. These results thus resolve the biochemical basis of essentiality for Mtb's ICLs and survival on fatty acids. However, our understanding of the pathways and physiologic functions they serve is incomplete. Enzymes catalyze reactions whose identities, rates, and directions are often difficult to determine and, where known, function within the context of complex and extensively interconnected physiologic networks (1). Thus, although recent genetic and biochemical approaches have made it possible to determine the essentiality of a given enzyme, our understanding of the biochemical mechanisms underlying their essentiality remains incomplete.Unlike the case for most microbial pathogens, humans serve as both host and reservoir for Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Within humans, Mtb resides within the biochemically stringent environment of the macrophage phagosome. Growing evidence has separately implicated Mtb's metabolic enzymes as a key determinant of its pathogenicity. Mtb's metabolic network thus appears to have evolved to serve interdependent physiologic and pathogenic roles (2, 3).Isocitrate lyase (ICL) is a metabolic enzyme used by bacteria to sustain growth on even-chain fatty acids through an anaplerotic pathway called the glyoxylate shunt. Mtb encodes two paralogous ICLs, each of which also functions as a methylisocitrate lyase (MCL), and serves a parallel pathway involved in the metabolism of propionyl CoA generated by β-oxidation of oddchain fatty acids, called the methylcitrate cycle. Mtb lacking both ICLs were shown to be incapable of either establishing or maintaining infection in a mouse model of pulmonary TB (4, 5). Although loss of ICL activity is expected to result in the inability to incorporate carbon from fatty acids (a form of starvation), simultaneous loss of MCL activity is predicted to result in the potentially toxic accumulation of propionyl-CoA metabolites (a form of intoxication). Here, we applied 13 C-based metabolomic tra...

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“…Although M. tuberculosis can inhibit maturation of the phagosome and limit its acidification to a pH of ϳ6.2 by excluding vacuolar proton-ATPase in immunologically naive macrophages, this block is relieved and the phagosomal compartment acidifies to a pH of 4.5 to 5.0 in gamma interferon (IFN-␥)-activated macrophages (56). Importantly, exposure of M. tuberculosis to a pH of Ͻ5.5 in vitro leads to growth arrest (57,58) and phenotypic tolerance to isoniazid (59).…”

Section: Stresses Simulating the Environment Within The Macrophage Phmentioning

confidence: 99%

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

Dutta

Karakousis

2014

Microbiol Mol Biol Rev

191

174

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SUMMARY The aim of this review is to present the current state of knowledge on human latent tuberculosis infection (LTBI) based on clinical studies and observations, as well as experimental in vitro and animal models. Several key terms are defined, including “latency,” “persistence,” “dormancy,” and “antibiotic tolerance.” Dogmas prevalent in the field are critically examined based on available clinical and experimental data, including the long-held beliefs that infection is either latent or active, that LTBI represents a small population of nonreplicating, “dormant” bacilli, and that caseous granulomas are the haven for LTBI. The role of host factors, such as CD4 + and CD8 + T cells, T regulatory cells, tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ), in controlling TB infection is discussed. We also highlight microbial regulatory and metabolic pathways implicated in bacillary growth restriction and antibiotic tolerance under various physiologically relevant conditions. Finally, we pose several clinically important questions, which remain unanswered and will serve to stimulate future research on LTBI.

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Acid Resistance inMycobacterium tuberculosis

Cited by 215 publications

References 102 publications

Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection

Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection

Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

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