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    Metabolic regulation of mycobacterial growth and antibiotic sensitivity

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    Authors
    Baek, Seung-Hun
    Li, Alice H.
    Sassetti, Christopher M.
    UMass Chan Affiliations
    Department of Microbiology and Physiological Systems
    Document Type
    Journal Article
    Publication Date
    2011-05-24
    Keywords
    Acetyl Coenzyme A
    Anaerobiosis
    Animals
    Antitubercular Agents
    Bacterial Load
    Bacterial Proteins
    Biosynthetic Pathways
    Citric Acid Cycle
    Drug Resistance, Bacterial
    Ethambutol
    Isoniazid
    Lung
    Mice
    Mice, Inbred C57BL
    Mutation
    Mycobacterium tuberculosis
    Pyrazinamide
    Spleen
    Stress, Physiological
    Triglycerides
    Tuberculosis, Pulmonary
    Life Sciences
    Medicine and Health Sciences
    Microbiology
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    Abstract
    Treatment of chronic bacterial infections, such as tuberculosis (TB), requires a remarkably long course of therapy, despite the availability of drugs that are rapidly bacteriocidal in vitro. This observation has long been attributed to the presence of bacterial populations in the host that are "drug-tolerant" because of their slow replication and low rate of metabolism. However, both the physiologic state of these hypothetical drug-tolerant populations and the bacterial pathways that regulate growth and metabolism in vivo remain obscure. Here we demonstrate that diverse growth-limiting stresses trigger a common signal transduction pathway in Mycobacterium tuberculosis that leads to the induction of triglyceride synthesis. This pathway plays a causal role in reducing growth and antibiotic efficacy by redirecting cellular carbon fluxes away from the tricarboxylic acid cycle. Mutants in which this metabolic switch is disrupted are unable to arrest their growth in response to stress and remain sensitive to antibiotics during infection. Thus, this regulatory pathway contributes to antibiotic tolerance in vivo, and its modulation may represent a novel strategy for accelerating TB treatment.
    Source
    Baek S-H, Li AH, Sassetti CM (2011) Metabolic Regulation of Mycobacterial Growth and Antibiotic Sensitivity. PLoS Biol 9(5): e1001065. doi:10.1371/journal.pbio.1001065. Link to article on publisher's site
    DOI
    10.1371/journal.pbio.1001065
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/39549
    PubMed ID
    21629732
    Related Resources
    Link to Article in PubMed
    Rights
    Copyright: © 2011 Baek et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pbio.1001065
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