Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy

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 compr...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Mycobacterium tuberculosis antibiotic resistance genetics Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8c96fac07b8d44018a07451d69e95d7a
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spelling	oai:doaj.org-article:8c96fac07b8d44018a07451d69e95d7a2021-11-15T16:22:09ZCommon Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy10.1128/mBio.00663-192150-7511https://doaj.org/article/8c96fac07b8d44018a07451d69e95d7a2019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00663-19https://doaj.org/toc/2150-7511ABSTRACT 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.Michelle M. BelleroseSeung-Hun BaekChuan-Chin HuangCaitlin E. MossEun-Ik KohMegan K. ProulxClare M. SmithRichard E. BakerJong Seok LeeSeokyong EumSung Jae ShinSang-Nae ChoMegan MurrayChristopher M. SassettiAmerican Society for MicrobiologyarticleMycobacterium tuberculosisantibiotic resistancegeneticsMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis antibiotic resistance genetics Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis antibiotic resistance genetics Microbiology QR1-502 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 Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy
description	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-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.
format	article
author	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
author_facet	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
author_sort	Michelle M. Bellerose
title	Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy
title_short	Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy
title_full	Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy
title_fullStr	Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy
title_full_unstemmed	Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy
title_sort	common variants in the glycerol kinase gene reduce tuberculosis drug efficacy
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/8c96fac07b8d44018a07451d69e95d7a
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Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy

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