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A data compendium of Mycobacterium tuberculosis antibiotic resistance

View ORCID ProfileAlice Brankin, View ORCID ProfileKerri M Malone, Ivan Barilar, Simone Battaglia, Emanuele Borroni, Angela Pires Brandao, Andrea Maurizio Cabibbe, Joshua Carter, Daniela Maria 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 Fu Gao, Jennifer Gardy, Saheer Gharbia, Kelen Teixeira Ghisi, Arash Ghodousi, Ana Luíza Gibertoni Cruz, Louis Grandjean, Clara Grazian, Ramona Groenheit, Jennifer L Guthrie, Wencong He, Harald Hoffmann, Sarah J Hoosdally, Martin Hunt, Zamin Iqbal, Nazir Ahmed 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, 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 Soli Nilgiriwala, Camus Nimmo, Nana Okozi, Rosangela Siqueira Oliveira, Shaheed Vally Omar, Nicholas Paton, Timothy EA Peto, Juliana Maira Watanabe Pinhata, Sara Plesnik, Zully M Puyen, Marie Sylvianne Rabodoarivelo, Niaina Rakotosamimanana, Paola MV Rancoita, Priti Rathod, Esther Robinson, Gillian Rodger, Camilla Rodrigues, Timothy C Rodwell, Aysha Roohi, David Santos-Lazaro, Sanchi Shah, Thomas Andreas Kohl, Grace Smith, Walter Solano, Andrea Spitaleri, Philip Supply, Utkarsha Surve, Sabira Tahseen, Nguyen Thuy Thuong Thuong, Guy Thwaites, Katharina Todt, Alberto Trovato, Christian Utpatel, Annelies Van Rie, Srinivasan Vijay, Timothy M Walker, A Sarah Walker, Robin 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
doi: https://doi.org/10.1101/2021.09.14.460274
Alice Brankin
4University of Oxford, Oxford, UK
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  • ORCID record for Alice Brankin
  • For correspondence: kmalone@ebi.ac.uk
Kerri M Malone
19EMBL-EBI, Hinxton, UK
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  • ORCID record for Kerri M Malone
  • For correspondence: kmalone@ebi.ac.uk
Ivan Barilar
29Research Center Borstel, Borstel, Germany
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Simone Battaglia
1IRCCS San Raffaele Scientific Institute, Milan, Italy
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Emanuele Borroni
1IRCCS San Raffaele Scientific Institute, Milan, Italy
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Angela Pires Brandao
2Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
3Institute Adolfo Lutz, São Paulo, Brazil
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Andrea Maurizio Cabibbe
1IRCCS San Raffaele Scientific Institute, Milan, Italy
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Joshua Carter
5Stanford University School of Medicine, Stanford, USA
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Daniela Maria Cirillo
1IRCCS San Raffaele Scientific Institute, Milan, Italy
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Pauline Claxton
6Scottish Mycobacteria Reference Laboratory, Edinburgh, UK
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David A Clifton
4University of Oxford, Oxford, UK
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Ted Cohen
7Yale School of Public Health, Yale, USA
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Jorge Coronel
8Universidad Peruana Cayetano Heredia, Lima, Perú
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Derrick W Crook
4University of Oxford, Oxford, UK
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Viola Dreyer
29Research Center Borstel, Borstel, Germany
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Sarah G Earle
4University of Oxford, Oxford, UK
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Vincent Escuyer
9Wadsworth Center, New York State Department of Health, Albany, USA
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Lucilaine Ferrazoli
3Institute Adolfo Lutz, São Paulo, Brazil
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Philip W Fowler
4University of Oxford, Oxford, UK
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George Fu Gao
10Chinese Center for Disease Control and Prevention, Beijing, China
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Jennifer Gardy
11Bill & Melinda Gates Foundation, Seattle, USA
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Saheer Gharbia
12UK Health Security Agency, London, UK
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Kelen Teixeira Ghisi
3Institute Adolfo Lutz, São Paulo, Brazil
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Arash Ghodousi
1IRCCS San Raffaele Scientific Institute, Milan, Italy
13Vita-Salute San Raffaele University, Milan, Italy
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Ana Luíza Gibertoni Cruz
4University of Oxford, Oxford, UK
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Louis Grandjean
33University College London, London, UK
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Clara Grazian
14University of New South Wales, Sydney, Australia
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Ramona Groenheit
44Public Health Agency of Sweden Solna, Sweden
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Jennifer L Guthrie
15The University of British Columbia, Vancouver, Canada
16Public Health Ontario, Toronto, Canada
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Wencong He
10Chinese Center for Disease Control and Prevention, Beijing, China
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Harald Hoffmann
17SYNLAB Gauting, Munich, Germany
18Institute of Microbiology and Laboratory Medicine, IMLred, WHO-SRL Gauting, Germany
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Sarah J Hoosdally
4University of Oxford, Oxford, UK
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Martin Hunt
19EMBL-EBI, Hinxton, UK
4University of Oxford, Oxford, UK
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Zamin Iqbal
19EMBL-EBI, Hinxton, UK
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Nazir Ahmed Ismail
20National Institute for Communicable Diseases, Johannesburg, South Africa
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Lisa Jarrett
21Public Health England, Birmingham, UK
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Lavania Joseph
20National Institute for Communicable Diseases, Johannesburg, South Africa
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Ruwen Jou
22Taiwan Centers for Disease Control, Taipei, Taiwan
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Priti Kambli
23Hinduja Hospital, Mumbai, India
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Rukhsar Khot
23Hinduja Hospital, Mumbai, India
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Jeff Knaggs
19EMBL-EBI, Hinxton, UK
4University of Oxford, Oxford, UK
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Anastasia Koch
24University of Cape Town, Cape Town, South Africa
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Donna Kohlerschmidt
9Wadsworth Center, New York State Department of Health, Albany, USA
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Samaneh Kouchaki
4University of Oxford, Oxford, UK
25University of Surrey, Guildford, UK
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Alexander S Lachapelle
4University of Oxford, Oxford, UK
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Ajit Lalvani
26Imperial College, London, UK
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Simon Grandjean Lapierre
27Université de Montréal, Canada
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Ian F Laurenson
6Scottish Mycobacteria Reference Laboratory, Edinburgh, UK
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Brice Letcher
19EMBL-EBI, Hinxton, UK
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22Taiwan Centers for Disease Control, Taipei, Taiwan
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10Chinese Center for Disease Control and Prevention, Beijing, China
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Dongxin Liu
10Chinese Center for Disease Control and Prevention, Beijing, China
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Ayan Mandal
28The Foundation for Medical Research, Mumbai, India
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44Public Health Agency of Sweden Solna, Sweden
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21Public Health England, Birmingham, UK
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24University of Cape Town, Cape Town, South Africa
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3Institute Adolfo Lutz, São Paulo, Brazil
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29Research Center Borstel, Borstel, Germany
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18Institute of Microbiology and Laboratory Medicine, IMLred, WHO-SRL Gauting, Germany
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30Africa Health Research Institute, Durban, South Africa
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1IRCCS San Raffaele Scientific Institute, Milan, Italy
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Nerges Mistry
28The Foundation for Medical Research, Mumbai, India
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David Moore
31London School of Hygiene and Tropical Medicine, London, UK
8Universidad Peruana Cayetano Heredia, Lima, Perú
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9Wadsworth Center, New York State Department of Health, Albany, USA
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20National Institute for Communicable Diseases, Johannesburg, South Africa
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32Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
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Stefan Niemann
29Research Center Borstel, Borstel, Germany
48German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems, Germany
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Kayzad Soli Nilgiriwala
28The Foundation for Medical Research, Mumbai, India
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33University College London, London, UK
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20National Institute for Communicable Diseases, Johannesburg, South Africa
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3Institute Adolfo Lutz, São Paulo, Brazil
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20National Institute for Communicable Diseases, Johannesburg, South Africa
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34National University of Singapore, Singapore
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4University of Oxford, Oxford, UK
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18Institute of Microbiology and Laboratory Medicine, IMLred, WHO-SRL Gauting, Germany
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35Instituto Nacional de Salud, Lima, Perú
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36Institut Pasteur de Madagascar, Antananarivo, Madagascar
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36Institut Pasteur de Madagascar, Antananarivo, Madagascar
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13Vita-Salute San Raffaele University, Milan, Italy
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21Public Health England, Birmingham, UK
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21Public Health England, Birmingham, UK
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4University of Oxford, Oxford, UK
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23Hinduja Hospital, Mumbai, India
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Timothy C Rodwell
37FIND, Geneva, Switzerland
38University of California, San Diego, USA
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4University of Oxford, Oxford, UK
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35Instituto Nacional de Salud, Lima, Perú
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28The Foundation for Medical Research, Mumbai, India
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29Research Center Borstel, Borstel, Germany
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21Public Health England, Birmingham, UK
12UK Health Security Agency, London, UK
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8Universidad Peruana Cayetano Heredia, Lima, Perú
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1IRCCS San Raffaele Scientific Institute, Milan, Italy
13Vita-Salute San Raffaele University, Milan, Italy
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Philip Supply
39Institut Pasteur de Lille, Lille, France
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Utkarsha Surve
23Hinduja Hospital, Mumbai, India
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Sabira Tahseen
40National TB Reference Laboratory, National TB Control Program, Islamabad, Pakistan
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Nguyen Thuy Thuong Thuong
32Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
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Guy Thwaites
32Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
4University of Oxford, Oxford, UK
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18Institute of Microbiology and Laboratory Medicine, IMLred, WHO-SRL Gauting, Germany
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29Research Center Borstel, Borstel, Germany
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41University of Antwerp, Antwerp, Belgium
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42University of Edinburgh, Edinburgh, UK
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4University of Oxford, Oxford, UK
32Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
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4University of Oxford, Oxford, UK
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43Stellenbosch University, Cape Town, South Africa
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44Public Health Agency of Sweden Solna, Sweden
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Maria Wijkander
44Public Health Agency of Sweden Solna, Sweden
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Robert J Wilkinson
45Wellcome Centre for Infectious Diseases Research in Africa, Cape Town, South Africa
46Francis Crick Institute, London, UK
26Imperial College, London, UK
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Daniel J Wilson
4University of Oxford, Oxford, UK
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Penelope Wintringer
19EMBL-EBI, Hinxton, UK
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Yu-Xin Xiao
22Taiwan Centers for Disease Control, Taipei, Taiwan
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Yang Yang
4University of Oxford, Oxford, UK
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Zhao Yanlin
10Chinese Center for Disease Control and Prevention, Beijing, China
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20National Institute for Communicable Diseases, Johannesburg, South Africa
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Baoli Zhu
47Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
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  • Abstract
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Abstract

The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a global collection of 15,211 Mycobacterium tuberculosis clinical isolates, all of which have undergone whole genome sequencing and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured. The isolates represent five major M. tuberculosis lineages originating from 23 countries across four continents. 6,814 isolates were found resistant to at least one drug, including 2,129 samples fully satisfy the clinical definitions of RR/MDR, pre-XDR or XDR. Resistance status to eight antitubercular drugs can be accurately predicted using a genetic mutation catalogue for over 90% of the isolates. Furthermore, we show the presence of suspected resistance conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid and linezolid. Finally, a case study of rifampicin mono-resistance is presented to showcase how this compendium could be used to advance our genetic understanding of rare resistance phenotypes and evaluate the likely performance of a widely used molecular diagnostic tool. It is hoped that this compendium, the largest M. tuberculosis matched phenotypic and genotypic dataset to date, will facilitate and inspire new research projects for years to come.

Competing Interest Statement

E.R. is employed by Public Health England and holds an honorary contract with Imperial College London. I.F.L. is Director of the Scottish Mycobacteria Reference Laboratory. S.N. receives funding from German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation, Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG)tion EXC 2167. P.S. is a consultant at Genoscreen. T.R. is funded by NIH and DoD and receives salary support from the non-profit organization FIND. T.R. is a co-founder, board member and shareholder of Verus Diagnostics Inc, a company that was founded with the intent of developing diagnostic assays. Verus Diagnostics was not involved in any way with data collection, analysis or publication of the results. T.R. has not received any financial support from Verus Diagnostics. UCSD Conflict of Interest office has reviewed and approved T.R.s role in Verus Diagnostics Inc. T.R. is a co-inventor of a provisional patent for a TB diagnostic assay (provisional patent #: 63/048.989). T.R. is a co-inventor on a patent associated with the processing of TB sequencing data (European Patent Application No. 14840432.0 & USSN 14/912,918). T.R. has agreed to donate all present and future interest in and rights to royalties from this patent to UCSD to ensure that he does not receive any financial benefits from this patent. S.S. is working and holding ESOPs at HaystackAnalytics Pvt. Ltd. (Product: Using whole genome sequencing for drug susceptibility testing for Mycobacterium tuberculosis). G.F.G. is listed as an inventor on patent applications for RBD-dimer-based CoV vaccines. The patents for RBD-dimers as protein subunit vaccines for SARS-CoV-2 have been licensed to Anhui Zhifei Longcom Biopharmaceutical Co. Ltd, China.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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A data compendium of Mycobacterium tuberculosis antibiotic resistance
Alice Brankin, Kerri M Malone, Ivan Barilar, Simone Battaglia, Emanuele Borroni, Angela Pires Brandao, Andrea Maurizio Cabibbe, Joshua Carter, Daniela Maria 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 Fu Gao, Jennifer Gardy, Saheer Gharbia, Kelen Teixeira Ghisi, Arash Ghodousi, Ana Luíza Gibertoni Cruz, Louis Grandjean, Clara Grazian, Ramona Groenheit, Jennifer L Guthrie, Wencong He, Harald Hoffmann, Sarah J Hoosdally, Martin Hunt, Zamin Iqbal, Nazir Ahmed 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, 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 Soli Nilgiriwala, Camus Nimmo, Nana Okozi, Rosangela Siqueira Oliveira, Shaheed Vally Omar, Nicholas Paton, Timothy EA Peto, Juliana Maira Watanabe Pinhata, Sara Plesnik, Zully M Puyen, Marie Sylvianne Rabodoarivelo, Niaina Rakotosamimanana, Paola MV Rancoita, Priti Rathod, Esther Robinson, Gillian Rodger, Camilla Rodrigues, Timothy C Rodwell, Aysha Roohi, David Santos-Lazaro, Sanchi Shah, Thomas Andreas Kohl, Grace Smith, Walter Solano, Andrea Spitaleri, Philip Supply, Utkarsha Surve, Sabira Tahseen, Nguyen Thuy Thuong Thuong, Guy Thwaites, Katharina Todt, Alberto Trovato, Christian Utpatel, Annelies Van Rie, Srinivasan Vijay, Timothy M Walker, A Sarah Walker, Robin 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
bioRxiv 2021.09.14.460274; doi: https://doi.org/10.1101/2021.09.14.460274
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A data compendium of Mycobacterium tuberculosis antibiotic resistance
Alice Brankin, Kerri M Malone, Ivan Barilar, Simone Battaglia, Emanuele Borroni, Angela Pires Brandao, Andrea Maurizio Cabibbe, Joshua Carter, Daniela Maria 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 Fu Gao, Jennifer Gardy, Saheer Gharbia, Kelen Teixeira Ghisi, Arash Ghodousi, Ana Luíza Gibertoni Cruz, Louis Grandjean, Clara Grazian, Ramona Groenheit, Jennifer L Guthrie, Wencong He, Harald Hoffmann, Sarah J Hoosdally, Martin Hunt, Zamin Iqbal, Nazir Ahmed 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, 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 Soli Nilgiriwala, Camus Nimmo, Nana Okozi, Rosangela Siqueira Oliveira, Shaheed Vally Omar, Nicholas Paton, Timothy EA Peto, Juliana Maira Watanabe Pinhata, Sara Plesnik, Zully M Puyen, Marie Sylvianne Rabodoarivelo, Niaina Rakotosamimanana, Paola MV Rancoita, Priti Rathod, Esther Robinson, Gillian Rodger, Camilla Rodrigues, Timothy C Rodwell, Aysha Roohi, David Santos-Lazaro, Sanchi Shah, Thomas Andreas Kohl, Grace Smith, Walter Solano, Andrea Spitaleri, Philip Supply, Utkarsha Surve, Sabira Tahseen, Nguyen Thuy Thuong Thuong, Guy Thwaites, Katharina Todt, Alberto Trovato, Christian Utpatel, Annelies Van Rie, Srinivasan Vijay, Timothy M Walker, A Sarah Walker, Robin 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
bioRxiv 2021.09.14.460274; doi: https://doi.org/10.1101/2021.09.14.460274

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