Department of Microbiology and Physiological Systems; Graduate School of Biomedical Sciences
Bacteria | Bacterial Infections and Mycoses | Enzymes and Coenzymes | Genetic Phenomena | Genetics and Genomics | Microbiology
Despite the administration of multiple drugs that are highly effective in vitro, tuberculosis (TB) treatment requires prolonged drug administration and is confounded by the emergence of drug-resistant strains. To understand the mechanisms that limit antibiotic efficacy, we performed a comprehensive genetic study to identify Mycobacterium tuberculosis genes that alter the rate of bacterial clearance in drug-treated mice. Several functionally distinct bacterial genes were found to alter bacterial clearance, and prominent among these was the glpK gene that encodes the glycerol-3-kinase enzyme that is necessary for glycerol catabolism. Growth on glycerol generally increased the sensitivity of M. tuberculosis to antibiotics in vitro, and glpK-deficient bacteria persisted during antibiotic treatment in vivo, particularly during exposure to pyrazinamide-containing regimens. Frameshift mutations in a hypervariable homopolymeric region of the glpK gene were found to be a specific marker of multidrug resistance in clinical M. tuberculosis isolates, and these loss-of-function alleles were also enriched in extensively drug-resistant clones. These data indicate that frequently observed variation in the glpK coding sequence produces a drug-tolerant phenotype that can reduce antibiotic efficacy and may contribute to the evolution of resistance.
IMPORTANCE: TB control is limited in part by the length of antibiotic treatment needed to prevent recurrent disease. To probe mechanisms underlying survival under antibiotic pressure, we performed a genetic screen for M. tuberculosis mutants with altered susceptibility to treatment using the mouse model of TB. We identified multiple genes involved in a range of functions which alter sensitivity to antibiotics. In particular, we found glycerol catabolism mutants were less susceptible to treatment and that common variation in a homopolymeric region in the glpK gene was associated with drug resistance in clinical isolates. These studies indicate that reversible high-frequency variation in carbon metabolic pathways can produce phenotypically drug-tolerant clones and have a role in the development of resistance.
Mycobacterium tuberculosis, antibiotic resistance, genetics
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Copyright © 2019 Bellerose et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
DOI of Published Version
MBio. 2019 Jul 30;10(4). pii: mBio.00663-19. doi: 10.1128/mBio.00663-19. Link to article on publisher's site
Bellerose MM, Baek S, Huang C, Moss CE, Koh E, Proulx MK, Smith CM, Baker RE, Lee JS, Eum S, Shin SJ, Cho S, Murray M, Sassetti CM. (2019). Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy. Open Access Articles. https://doi.org/10.1128/mBio.00663-19. Retrieved from https://escholarship.umassmed.edu/oapubs/3924
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This work is licensed under a Creative Commons Attribution 4.0 License.