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, Michelle M.; Baek, Seung-Hun; Huang, Chuan-Chin; Moss, Caitlin E.; Koh, Eun-Ik; Proulx, Megan K.; Smith, Clare M.; Baker, Richard E.; Lee, Jong Seok; Eum, Seokyong; Shin, Sung Jae; Cho, Sang-Nae; Murray, Megan; and Sassetti, Christopher M., "Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy" (2019). Open Access Articles. 3924.
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This work is licensed under a Creative Commons Attribution 4.0 License.