Metabolic Regulation of Mycobacterial Growth and Antibiotic Sensitivity
Open Access
- 24 May 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Biology
- Vol. 9 (5), e1001065
- https://doi.org/10.1371/journal.pbio.1001065
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. Despite the availability of antibiotics that rapidly kill bacteria in vitro, the treatment of chronic bacterial infections, such as tuberculosis, requires long-term drug therapy. The reasons for this are unclear, but many have hypothesized that the slow replication and concomitantly low metabolic rate of bacteria in the host environment produce an “antibiotic-tolerant” state. We have tested this hypothesis by identifying the bacterial pathways responsible for slowing the growth and metabolism of Mycobacterium tuberculosis in response to stress. We found that diverse growth-limiting stresses trigger a common signal transduction pathway that slows bacterial growth by redirecting cellular carbon fluxes away from central metabolic pathways and towards storage. Disruption of this metabolic switch increased the antibiotic sensitivity of the bacterium during infection, verifying that this response significantly contributes to antibiotic tolerance and suggesting new strategies for accelerating therapy.Keywords
This publication has 32 references indexed in Scilit:
- Carbon flux rerouting during Mycobacterium tuberculosis growth arrestMolecular Microbiology, 2010
- Signals of growth regulation in bacteriaCurrent Opinion in Microbiology, 2009
- Phthiocerol Dimycocerosate Transport Is Required for Resisting Interferon‐γ–Independent ImmunityThe Journal of Infectious Diseases, 2009
- Effects of Antibiotics and a Proto-Oncogene Homolog on Destruction of Protein Translocator SecYScience, 2009
- A replication clock for Mycobacterium tuberculosisNature Medicine, 2009
- PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO ReleaseScience, 2008
- The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosisProceedings of the National Academy of Sciences of the United States of America, 2008
- Mycobacterial persistence requires the utilization of host cholesterolProceedings of the National Academy of Sciences of the United States of America, 2008
- Lipid composition and transcriptional response of Mycobacterium tuberculosis grown under iron-limitation in continuous culture: identification of a novel wax esterMicrobiology, 2007
- Identification of a diacylglycerol acyltransferase gene involved in accumulation of triacylglycerol in Mycobacterium tuberculosis under stressMicrobiology, 2006