Genomic signatures of pre-resistance in Mycobacterium tuberculosis

Arturo Torres Ortiz, Jorge Coronel, Julia Rios Vidal, Cesar Bonilla, David A. J. Moore, Robert H. Gilman, Francois Balloux, Onn Min Kon, Xavier Didelot and Louis Grandjean ()
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Arturo Torres Ortiz: Imperial College London, Department of Infectious Diseases
Jorge Coronel: Universidad Peruana Cayetano Heredia
Julia Rios Vidal: Unidad Técnica de Tuberculosis MDR, Ministerio de Salud
Cesar Bonilla: Unidad Técnica de Tuberculosis MDR, Ministerio de Salud
David A. J. Moore: London School of Hygiene and Tropical Medicine
Robert H. Gilman: Johns Hopkins Bloomberg School of Public Health
Francois Balloux: UCL Genetics Institute
Onn Min Kon: Imperial College London
Xavier Didelot: University of Warwick, School of Life Sciences and Department of Statistics
Louis Grandjean: Imperial College London, Department of Infectious Diseases

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Recent advances in bacterial whole-genome sequencing have resulted in a comprehensive catalog of antibiotic resistance genomic signatures in Mycobacterium tuberculosis. With a view to pre-empt the emergence of resistance, we hypothesized that pre-existing polymorphisms in susceptible genotypes (pre-resistance mutations) could increase the risk of becoming resistant in the future. We sequenced whole genomes from 3135 isolates sampled over a 17-year period. After reconstructing ancestral genomes on time-calibrated phylogenetic trees, we developed and applied a genome-wide survival analysis to determine the hazard of resistance acquisition. We demonstrate that M. tuberculosis lineage 2 has a higher risk of acquiring resistance than lineage 4, and estimate a higher hazard of rifampicin resistance evolution following isoniazid mono-resistance. Furthermore, we describe loci and genomic polymorphisms associated with a higher risk of resistance acquisition. Identifying markers of future antibiotic resistance could enable targeted therapy to prevent resistance emergence in M. tuberculosis and other pathogens.

Date: 2021
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DOI: 10.1038/s41467-021-27616-7

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