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

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Rodrigues, Camilla ; Moore, David ; Crook, Derrick W. ; Cirillo, Daniela M. ; Fowler, Philip W. ; Iqbal, Zamin ; Ismail, Nazir A. ; Mistry, Nerges ; Niemann, Stefan ; Peto, Tim E. A. ; Thwaites, Guy ; Walker, A. Sarah ; MWalker, Timothy ; Wilson, Daniel J. ; Earle, Sarah G. ; Grazian, Clara ; Hunt, Martin ; Knaggs, Jeff ; CRyPTIC Consortium

• Tipo de documento: Artigo Científico
• Fonte: PLOS BIOLOGY; v. 20, n. 8, p. 27-pg., 2022-08-01.

Resumo

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 oligonucleotidebased 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 a- 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. (AU)

• Processo FAPESP: 12/51756-5 - Avaliação de desenvolvimento de métodos rápidos para o diagnóstico da tuberculose multirresistente e extensivamente resistente e aplicabilidade em um laboratório de referência
• Beneficiário: Lucilaine Ferrazoli
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisa em Políticas Públicas para o SUS
• Processo FAPESP: 17/16082-7 - Caracterização de mutações em isolados clínicos de Mycobacterium tuberculosis resistentes aos fármacos de 1ª e 2ª linha e relação entre as mutações e os níveis fenotípicos de resistência à isoniazida.
• Beneficiário: Rosangela Siqueira de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Regular