Genomic signatures of pre-resistance in Mycobacterium tuberculosis

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. Signals of antimicrobial resistance in pathogen genomes may be detectable before the organism evolves an antimicrobial resistance phenotype. Here, the authors investigate this hypothesis using Mycobacterium tuberculosis data from Peru and identify candidate pre-resistance markers.

Automated summary

Recent advances in bacterial whole-genome sequencing have led to a comprehensive catalog of antibiotic resistance genomic signatures in Mycobacterium tuberculosis. The study found that certain genotypes in M. tuberculosis are more prone to acquiring resistance, with specific loci and genomic polymorphisms associated with a higher risk of resistance acquisition. By identifying markers of future antibiotic resistance, targeted therapy could be implemented to prevent resistance emergence in M. tuberculosis and other pathogens.