Common Variants in the Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy.

MBio
Michelle M BelleroseChristopher M Sassetti

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-t...Continue Reading

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Citations

Jun 3, 2020·Journal of Bacteriology·Meredith WhitakerSabine Ehrt
Feb 23, 2020·Proceedings of the National Academy of Sciences of the United States of America·Roger Vargas, Maha R Farhat
Sep 29, 2020·Frontiers in Microbiology·Francesca BoldrinRiccardo Manganelli
Jun 26, 2020·Science Translational Medicine·Sarah M SchraderCarl Nathan
Oct 30, 2020·Molecular Biology and Evolution·Yair E Gatt, Hanah Margalit
Dec 16, 2020·FEMS Microbiology Reviews·Rhastin A D CastroSebastien Gagneux
Feb 23, 2021·Frontiers in Microbiology·Anna Allué-GuardiaJordi B Torrelles
Oct 16, 2020·Clinical Microbiology Reviews·Sander N GoossensAnnelies Van Rie
Apr 22, 2021·Proceedings of the National Academy of Sciences of the United States of America·Qingyun LiuQian Gao
May 5, 2021·Molecular Systems Biology·Khushboo BorahDany J V Beste
Aug 8, 2021·Journal of Clinical Medicine·Annelies W MesmanMegan B Murray
Aug 25, 2021·Proceedings of the National Academy of Sciences of the United States of America·Juhyeon LimHyungjin Eoh

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Datasets Mentioned

BETA
GEMMA

Methods Mentioned

BETA
PCR

Software Mentioned

GATK GenotypeGVCFs
PHYLIP retree
GATK UnifiedGenotyper
picard
SAMtools
PHYML
GATK
GATK BaseRecalibrator
TNseq
GATK Realigner Target Creator

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