Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach

作者：Ivan Barilar, Simone Battaglia, Emanuele Borroni, Angela Pires Brandão, Alice Brankin, Andrea Maurizio Cabibbe, Joshua Carter, Darren Chetty, Daniela María Cirillo, Pauline Claxton, David A. Clifton, Ted Cohen, Jorge Coronel, Derrick W. Crook, Viola Dreyer, Sarah G. Earle, Vincent Escuyer, Lucilaine Ferrazoli, Philip W. Fowler, George F. Gao, Jennifer L. Gardy, Saheer E. Gharbia, Kelen Teixeira Ghisi, Arash Ghodousi, Ana Lúıza Gibertoni Cruz, Louis Grandjean, Clara Grazian, Ramona Groenheit, Jennifer L. Guthrie, Wencong He, Harald Hoffmann, Sarah Hoosdally, Martin Hunt, Zamin Iqbal, Nazir Ismail, Lisa Jarrett, Lavania Joseph, Ruwen Jou, Priti Kambli, Rukhsar Khot, Jeff Knaggs, Anastasia Koch, Donna Kohlerschmidt, Samaneh Kouchaki, Alexander S. Lachapelle, Ajit Lalvani, Simon Grandjean Lapierre, Ian F. Laurenson, Brice Letcher, Wan-Hsuan Lin, Chunfa Liu, Dongxin Liu, Kerri M. Malone, Ayan Mandal, Mikael Mansjö, Daniela Matias, Graeme Meintjes, Flávia de Freitas Mendes, Matthias Merker, Marina Mihalic, James Millard, Paolo Miotto, Nerges Mistry, David Moore, Kimberlee A. Musser, Dumisani Ngcamu, Hoang Ngoc Nhung, Stefan Niemann, Kayzad Nilgiriwala, Camus Nimmo, Max R. O’Donnell, Nana Okozi, Rosângela Siqueira de Oliveira, Shaheed Vally Omar, Nicholas I. Paton, Tim Peto, Juliana Maíra Watanabe Pinhata, Sara Plesnik, Zully M. Puyén, Marie Sylvianne Rabodoarivelo, Niaina Rakotosamimanana, Paola M. V. Rancoita, Priti Rathod, Esther Robinson, Gillian Rodger, Camilla Rodrigues, Timothy C. Rodwell, Aysha Roohi, David Santos-Lázaro, Sanchi Shah, Grace Smith, Thomas A. Kohl, Walter Solano, Andrea Spitaleri, Adrie J. C. Steyn, Philip Supply, Utkarsha Surve, Sabira Tahseen, Nguyễn Thụy Thương Thương, Guy Thwaites, Katharina Todt, Alberto Trovato, Christian Utpatel, Annelies Van Rie, Srinivasan Vijay, A Sarah Walker, A Sarah Walker, Robin M. Warren, Jim Werngren, Maria Wijkander, Robert J. Wilkinson, Daniel J. Wilson, Penelope Wintringer, Yu-Xin Xiao, Yang Yang, Zhao Yanlin, Shen-Yuan Yao, Baoli Zhu · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-023-44325-5 · 被引用次数：47 · 研究领域：Tuberculosis Research and Epidemiology、Mycobacterium research and diagnosis、vaccines and immunoinformatics approaches

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.