Genomic Signatures of Pre-Resistance in Mycobacterium tuberculosis

Abstract

\n Recent advances in bacterial whole-genome sequencing have resulted in the identification of a comprehensive catalogue of genomic signatures of antibiotic resistance in Mycobacterium tuberculosis. With a view to pre-empting the emergence of drug-resistance, we hypothesized that pre-existing balanced polymorphisms in drug susceptible genotypes (“pre-resistance mutations”) could increase the risk of acquiring antimicrobial resistance in the future.\nIn order to identify a pathogen genomic signature of future drug resistance we undertook whole-genome sequencing on 3135 culture positive isolates from different patients sampled over a 17-year period in Lima, Peru.\nReconstructing ancestral whole genomes on time-calibrated phylogenetic trees we identified no single drug resistance in Peru predating 1940. Moving forward in evolutionary time through the phylogenetic tree from 1940, we apply a novel genome-wide survival analysis to determine the hazard of drug resistance acquisition at the level of lineage, mono-resistance state, and single-nucleotide polymorphism. We demonstrate that lineage 2 has a significantly higher incidence of drug resistance acquisition than lineage 4 (HR 3.36, 95% CI 2.10 - 5.38,p-value =4.25×10-7) and estimate that the hazard of evolving rifampicin following isoniazid resistance acquisition is 14 times that of genomes with a susceptible background (HR 14.45,95% CI 8.46 - 15.50, p-value<10−15). Our findings are validated in a separate publicly available dataset from Samara, Russia. After controlling for population structure, we also show that a deletion in a gene coding for the cell surface protein lppP predisposes to the acquisition of drug resistance in susceptible genotypes (HR 6.71, 95% CI4.82-11.22, p-value =1.17×10−9).\nPrediction of future drug resistance in susceptible pathogens together with targeted expanded therapy has the potential to prevent drug resistance emergence in Mycobacterium tuberculosis and other pathogens. Prospective cohort studies of participants with and with-out these polymorphisms should be undertaken with a view to implementing personalized pathogen genomic therapy. This approach could be employed to preempt and prevent the emergence of drug resistance and other important traits in other organisms.