Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex.

Genome Medicine
Matthias MerkerStefan Niemann

Abstract

A comprehensive understanding of the pre-existing genetic variation in genes associated with antibiotic resistance in the Mycobacterium tuberculosis complex (MTBC) is needed to accurately interpret whole-genome sequencing data for genotypic drug susceptibility testing (DST). We investigated mutations in 92 genes implicated in resistance to 21 anti-tuberculosis drugs using the genomes of 405 phylogenetically diverse MTBC strains. The role of phylogenetically informative mutations was assessed by routine phenotypic DST data for the first-line drugs isoniazid, rifampicin, ethambutol, and pyrazinamide from a separate collection of over 7000 clinical strains. Selected mutations/strains were further investigated by minimum inhibitory concentration (MIC) testing. Out of 547 phylogenetically informative mutations identified, 138 were classified as not correlating with resistance to first-line drugs. MIC testing did not reveal a discernible impact of a Rv1979c deletion shared by M. africanum lineage 5 strains on resistance to clofazimine. Finally, we found molecular evidence that some MTBC subgroups may be hyper-susceptible to bedaquiline and clofazimine by different loss-of-function mutations affecting a drug efflux pump subunit (MmpL5...Continue Reading

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Citations

Jun 24, 2020·Antimicrobial Agents and Chemotherapy·Claudio U KöserPaolo Miotto
Sep 2, 2020·Antimicrobial Agents and Chemotherapy·Martina L ReichmuthPeter M Keller
Mar 5, 2021·Journal of Clinical Microbiology·Darshaalini NadarajanFlorian P Maurer
Mar 17, 2021·Antimicrobial Agents and Chemotherapy·Samuel J ModlinFaramarz Valafar
May 25, 2021·Computational and Structural Biotechnology Journal·Pooja SinghSeyed E Hasnain
Apr 27, 2021·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Hans-Peter GrobbelStefan Niemann
May 12, 2021·Antimicrobial Agents and Chemotherapy·Simone MokMargaret M Fitzgibbon

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Methods Mentioned

BETA
PCR

Software Mentioned

Fast Tree
FigTree
EpiCenter TBeXiST
GATK
Samtools
Fastq
BWA

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