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Genomic signatures of pre-resistance in Mycobacterium tuberculosis

Author

Listed:
  • 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
    Universidad Privada San Juan Bautista)

  • 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
    UCL Department of Infection, Institute of Child Health)

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.

Suggested Citation

  • Arturo Torres Ortiz & Jorge Coronel & Julia Rios Vidal & Cesar Bonilla & David A. J. Moore & Robert H. Gilman & Francois Balloux & Onn Min Kon & Xavier Didelot & Louis Grandjean, 2021. "Genomic signatures of pre-resistance in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27616-7
    DOI: 10.1038/s41467-021-27616-7
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    Cited by:

    1. Gladys Estigarribia Sanabria & Guillermo Sequera & Sarita Aguirre & Julieta Méndez & Paulo César Pereira Santos & Natalie Weiler Gustafson & Margarita Godoy & Analía Ortiz & Cynthia Cespedes & Gloria , 2023. "Phylogeography and transmission of Mycobacterium tuberculosis spanning prisons and surrounding communities in Paraguay," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Chloé Loiseau & Etthel M. Windels & Sebastian M. Gygli & Levan Jugheli & Nino Maghradze & Daniela Brites & Amanda Ross & Galo Goig & Miriam Reinhard & Sonia Borrell & Andrej Trauner & Anna Dötsch & Ru, 2023. "The relative transmission fitness of multidrug-resistant Mycobacterium tuberculosis in a drug resistance hotspot," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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