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

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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 Luiza ; 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 ; Mansjoe, Mikael ; Calisto Matias, Daniela Vicente Lucena ; Meintjes, Graeme ; de Freitas Mendes, Flavia ; 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

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 15, n. 1, p. 13-pg., 2024-01-12.

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. (AU)

• FAPESP's process: 12/51756-5 - Performance of methods for diagnosis of multidrug-resistant tuberculosis and Extensively Resistant. Applicability in a Reference Laboratory
• Grantee: Lucilaine Ferrazoli
• Support Opportunities: Research Grants - Research in Public Policies for the National Health Care System (PP-SUS)
• FAPESP's process: 17/16082-7 - Characterization of mutations in clinical isolates of Mycobacterium tuberculosis resistant to 1st and 2nd line drugs and the relationship between mutations and phenotypic resistance levels to isoniazid.
• Grantee: Rosangela Siqueira de Oliveira
• Support Opportunities: Regular Research Grants