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.
Footnotes
Figure 6 was duplicated as figure 4 in the manuscript.
