Genomic signatures of pre-resistance in Mycobacterium tuberculosis.

Torres Ortiz, AORCID logo; Coronel, J; Vidal, JR; Bonilla, C; Moore, DAORCID logo; Gilman, RH; Balloux, FORCID logo; Kon, OM; Didelot, XORCID logo; Grandjean, LORCID logo and (2021) Genomic signatures of pre-resistance in Mycobacterium tuberculosis. Nature Communications, 12 (1). 7312-. DOI: 10.1038/s41467-021-27616-7
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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.


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