Genome-wide association studies of global Mycobacterium tuberculosis resistance to 13 antimicrobials in 10,228 genomes identify new resistance mechanisms

• Published in: PLoS biology Vol. 20; no. 8; p. e3001755
• Main Authors: Consortium, The Cryptic, Supply, Philip
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.08.2022; Public Library of Science (PLoS)
• Subjects: Anti-Infective Agents - pharmacology; Antimicrobial agents; Antimicrobial resistance; Antitubercular Agents - pharmacology; Binding sites; Biology and Life Sciences; Clofazimine; Confidence intervals; Cross-resistance; Drug resistance; Drug resistance in microorganisms; Drugs; Gene sequencing; Genetic aspects; Genetic diversity; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Health risks; Heritability; Humans; Isoniazid; Life Sciences; Linezolid; Medicine and Health Sciences; Microbial Sensitivity Tests; Minimum inhibitory concentration; Mutation; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Oligonucleotides; Phenotypes; Public health; rRNA; rRNA 23S; Short Reports; Tuberculosis; Tuberculosis, Multidrug-Resistant - drug therapy; Tuberculosis, Multidrug-Resistant - genetics; Tuberculosis, Multidrug-Resistant - microbiology; Whole genome sequencing; United Kingdom
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3001755

The emergence of drug-resistant tuberculosis is a major global public health concern that threatens the ability to control the disease. Whole-genome sequencing as a tool to rapidly diagnose resistant infections can transform patient treatment and clinical practice. While resistance mechanisms are well understood for some drugs, there are likely many mechanisms yet to be uncovered, particularly for new and repurposed drugs. We sequenced 10,228 Mycobacterium tuberculosis (MTB) isolates worldwide and determined the minimum inhibitory concentration (MIC) on a grid of 2-fold concentration dilutions for 13 antimicrobials using quantitative microtiter plate assays. We performed oligopeptide- and oligonucleotide-based genome-wide association studies using linear mixed models to discover resistance-conferring mechanisms not currently catalogued. Use of MIC over binary resistance phenotypes increased sample heritability for the new and repurposed drugs by 26% to 37%, increasing our ability to detect novel associations. For all drugs, we discovered uncatalogued variants associated with MIC, including in the Rv1218c promoter binding site of the transcriptional repressor Rv1219c (isoniazid), upstream of the vapBC20 operon that cleaves 23S rRNA (linezolid) and in the region encoding an α-helix lining the active site of Cyp142 (clofazimine, all p < 10-7.7). We observed that artefactual signals of cross-resistance could be unravelled based on the relative effect size on MIC. Our study demonstrates the ability of very large-scale studies to substantially improve our knowledge of genetic variants associated with antimicrobial resistance in M. tuberculosis.