Common variants in the glycerol kinase gene reduce tuberculosis drug efficacy

Michelle M. Bellerose, Seung Hun Baek, Chuan Chin Huang, Caitlin E. Moss, Eun Ik Koh, Megan K. Proulx, Clare M. Smith, Richard E. Baker, Jong Seok Lee, Seokyong Eum, Sung Jae Shin, Sang Nae Cho, Megan Murray, Christopher M. Sassetti

Research output: Contribution to journalArticle

Abstract

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-offunction 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.

Original languageEnglish
Article numbere00663-19
JournalmBio
Volume10
Issue number4
DOIs
Publication statusPublished - 2019 Jul 1

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Glycerol Kinase
Tuberculosis
Mycobacterium tuberculosis
Pharmaceutical Preparations
Genes
Anti-Bacterial Agents
Glycerol
Pyrazinamide
Bacterial Genes
Frameshift Mutation
Multiple Drug Resistance
Clone Cells
Alleles
Bacteria
Phenotype
Enzymes
Growth

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Virology

Cite this

Bellerose, M. M., Baek, S. H., Huang, C. C., Moss, C. E., Koh, E. I., Proulx, M. K., ... Sassetti, C. M. (2019). Common variants in the glycerol kinase gene reduce tuberculosis drug efficacy. mBio, 10(4), [e00663-19]. https://doi.org/10.1128/mBio.00663-19
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 ; Sassetti, Christopher M. / Common variants in the glycerol kinase gene reduce tuberculosis drug efficacy. In: mBio. 2019 ; Vol. 10, No. 4.
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Bellerose, MM, Baek, SH, Huang, CC, Moss, CE, Koh, EI, Proulx, MK, Smith, CM, Baker, RE, Lee, JS, Eum, S, Shin, SJ, Cho, SN, Murray, M & Sassetti, CM 2019, 'Common variants in the glycerol kinase gene reduce tuberculosis drug efficacy', mBio, vol. 10, no. 4, e00663-19. https://doi.org/10.1128/mBio.00663-19

Common variants in the glycerol kinase gene reduce tuberculosis drug efficacy. / 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; Sassetti, Christopher M.

In: mBio, Vol. 10, No. 4, e00663-19, 01.07.2019.

Research output: Contribution to journalArticle

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AU - Cho, Sang Nae

AU - Murray, Megan

AU - Sassetti, Christopher M.

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Bellerose MM, Baek SH, Huang CC, Moss CE, Koh EI, Proulx MK et al. Common variants in the glycerol kinase gene reduce tuberculosis drug efficacy. mBio. 2019 Jul 1;10(4). e00663-19. https://doi.org/10.1128/mBio.00663-19