ArticlePLoS biology2022
Genome-wide association studies of global Mycobacterium tuberculosis resistance to 13 antimicrobials in 10,228 genomes identify new resistance mechanisms.
Article in PLoS biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 82 citations in OpenAlex.
- In Host Mutational Adaptation of Mycobacterium Tuberculosis Complex Strains During Tuberculosis Infection.The Journal of infectious diseases · 2026Pooled it
- Population-level genome sequencing reveals distinctmSystems · 2026Article
- Resistance potentiators: Evolutionary catalysts of antibiotic resistance.PLoS biology · 2026Article
- Genome scale CRISPRi reveals both shared and strain-specific vulnerabilities in genetically diverse drug-resistant strains of Mycobacterium tuberculosis.Nature communications · 2026Article
- Convolutional neural networks quantify antibiotic resistance in Mycobacterium tuberculosis with diagnostic grade accuracy and predict treatment response.Nature communications · 2026Article
- PE/PPE proteins contribute to Mycobacterium tuberculosis drug resistance.Nature communications · 2026Article
- Population-level genome sequencing reveals distinct Mycobacterium tuberculosis intrahost mutational trajectories in simian immunodeficiency virus co-infected and antiretroviral treated non-human primates.bioRxiv : the preprint server for biology · 2026Article
- BaGPipe: an automated, reproducible, and flexible pipeline for bacterial genome-wide association studies.BMC microbiology · 2026Article
- A tiled amplicon protocol for culture-free whole-genome sequencing ofJournal of clinical microbiology · 2026Article
- Drug resistance mechanisms inFrontiers in pharmacology · 2026Review
- Unraveling Epistatic Interactions Between Sites Under Drug-Dependent Selection in the Mycobacterium tuberculosis Genome.Molecular biology and evolution · 2025Article
- Machine learning and statistical inference in microbial population genomics.Genome biology · 2025Review
- Bacterial Systematic Genetics and Integrated Multi-Omics: Beyond Static Genomics Toward Predictive Models.International journal of molecular sciences · 2025Review
- Sentinel-Site-Based Surveillance ofAntibiotics (Basel, Switzerland) · 2025Article
- Bacterial genome-wide association studies: exploring the genetic variation underlying bacterial phenotypes.Applied and environmental microbiology · 2025Review
- An improved catalogue for whole-genome sequencing prediction of bedaquiline resistance inMicrobial genomics · 2025Article
- Reference-Free Variant Calling with Local Graph Construction with ska lo (SKA).Molecular biology and evolution · 2025Article
- Demixer: a probabilistic generative model to delineate different strains of a microbial species in a mixed infection sample.Bioinformatics (Oxford, England) · 2025Article
- Advantages of updated WHO mutation catalog combined with existing whole-genome sequencing-based approaches for Mycobacterium tuberculosis resistance prediction.Genome medicine · 2025Article
- Enhanced diagnosis of multi-drug-resistant microbes using group association modeling and machine learning.Nature communications · 2025Article
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Authors and funding
1 author at 1 institution in 1 country.
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Abstract
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.
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