Metabolic regulation of mycobacterial growth and antibiotic sensitivity
UMass Chan Affiliations
Department of Microbiology and Physiological SystemsDocument Type
Journal ArticlePublication Date
2011-05-24Keywords
Acetyl Coenzyme AAnaerobiosis
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
Metadata
Show full item recordAbstract
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 siteDOI
10.1371/journal.pbio.1001065Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39549PubMed ID
21629732Related Resources
Link to Article in PubMedRights
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