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. , Gao George Fu , Gardy Jennifer , Gharbia Saheer , Ghisi Kelen Teixeira , Ghodousi Arash , Gibertoni Cruz Ana Luíza , Grandjean Louis , Grazian Clara , Groenheit Ramona , Guthrie Jennifer L. , He Wencong , Hoffmann Harald , Hoosdally Sarah J. , Hunt Martin , Iqbal Zamin , Ismail Nazir Ahmed , Jarrett Lisa , Joseph Lavania , Jou Ruwen , Kambli Priti , Khot Rukhsar , Knaggs Jeff , Koch Anastasia , Kohlerschmidt Donna , Kouchaki Samaneh , Lachapelle Alexander S. , Lalvani Ajit , Lapierre Simon Grandjean , Laurenson Ian F. , Letcher Brice , Lin Wan-Hsuan , Liu Chunfa , Liu Dongxin , Malone Kerri M. , Mandal Ayan , Mansjö Mikael , Calisto Matias Daniela Vicente Lucena , Meintjes Graeme , de Freitas Mendes Flávia , Merker Matthias , Mihalic Marina , Millard James , Miotto Paolo , Mistry Nerges , Moore David , Musser Kimberlee A. , Ngcamu Dumisani , Nhung Hoang Ngoc , Niemann Stefan , Nilgiriwala Kayzad Soli , Nimmo Camus , O’Donnell Max , Okozi Nana , Oliveira Rosangela Siqueira , Omar Shaheed Vally , Paton Nicholas , Peto Timothy E. A. , Pinhata Juliana Maira Watanabe , Plesnik Sara , Puyen Zully M. , Rabodoarivelo Marie Sylvianne , Rakotosamimanana Niaina , Rancoita Paola M. V. , Rathod Priti , Robinson Esther Rhiannon , Rodger Gillian , Rodrigues Camilla , Rodwell Timothy C. , Roohi Aysha , Santos-Lazaro David , Shah Sanchi , Smith Grace , Kohl Thomas Andreas , Solano Walter , Spitaleri Andrea , Steyn Adrie J. C. , Supply Philip , Surve Utkarsha , Tahseen Sabira , Thuong Nguyen Thuy Thuong , Thwaites Guy , Todt Katharina , Trovato Alberto , Utpatel Christian , Van Rie Annelies , Vijay Srinivasan , Walker A. Sarah , Walker Timothy M. , Warren Robin , Werngren Jim , Wijkander Maria , Wilkinson Robert J. , Wilson Daniel J. , Wintringer Penelope , Xiao Yu-Xin , Yang Yang , Yanlin Zhao , Yao Shen-Yuan , Zhu Baoli 
Published: January 2024

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.