Metabolic regulation of mycobacterial growth and antibiotic sensitivity
UMass Chan AffiliationsDepartment of Microbiology and Physiological Systems
KeywordsAcetyl Coenzyme A
Citric Acid Cycle
Drug Resistance, Bacterial
Mice, Inbred C57BL
Medicine and Health Sciences
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AbstractTreatment 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.
SourceBaek 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
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/39549
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RightsCopyright: © 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.