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- Title
Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach.
- Authors
The CRyPTIC Consortium; Barilar, Ivan; Battaglia, Simone; Borroni, Emanuele; Brandao, Angela Pires; Brankin, Alice; Cabibbe, Andrea Maurizio; Carter, Joshua; Chetty, Darren; Cirillo, Daniela Maria; Claxton, Pauline; Clifton, David A.; Cohen, Ted; Coronel, Jorge; Crook, Derrick W.; Dreyer, Viola; Earle, Sarah G.; Escuyer, Vincent; Ferrazoli, Lucilaine; Fowler, Philip W.
- Abstract
The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis. However, molecular diagnostics to date have focused largely on first-line drugs and predicting susceptibilities in a binary manner (classifying strains as either susceptible or resistant). Here, we used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration (MIC) in 15,211 Mycobacterium tuberculosis clinical isolates from 23 countries across five continents. We identified 492 unique MIC-elevating variants across 13 drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms. Molecular diagnostics for tuberculosis have focused on predicting drug susceptibilities in a binary manner (i.e., strains are either susceptible or resistant). Here, CRyPTIC Consortium researchers use whole genome sequencing and a quantitative assay to identify associations between genomic mutations and minimum inhibitory concentrations in over 15,000 Mycobacterium tuberculosis clinical isolates.
- Subjects
WORLD Health Organization; MYCOBACTERIUM tuberculosis; DRUG resistance in bacteria; WHOLE genome sequencing; NUCLEOTIDE sequencing; DRUG resistance; DISEASE susceptibility
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-44325-5