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.
Highlights
We found no significant association between M. tuberculosis sublineages and HIV (Supplementary Fig. 11a) and smear positivity (Supplementary Fig. 11b) in a logistic regression model (n = 2133, all p-values > 0.1)
We found no significant association between M. tuberculosis sublineages and previous treatment with antituberculous drugs in a logistic regression model (n = 2236, all p-values > 0.1), suggesting that the between lineage differences in drug resistance acquisition observed in the survival analysis are not confounded by a differential distribution of antibiotics between sublineages (Supplementary Fig. 11d)
Using an ancestral state genome-wide survival analysis to move in time through the phylogenetic tree, we show that M. tuberculosis is predisposed to acquire drug resistance mutations at the lineage level, after mono-resistance, and at the level of nucleotide polymorphisms
Summary
Population structure, genomic analysis, and patient demographics. A total of 3432 M. tuberculosis genomes from Lima (Peru) were analyzed, of which 3135 passed genomic quality filters. The remaining samples were collected from cohort studies covering a 17-year period of research in the regions of Lima and Callao in order to achieve a sufficient temporal span in our sampling window (Supplementary Fig. 1). To study the temporal dynamics of drug resistance acquisition at the population level, the maximum likelihood phylogeny was timecalibrated using the sampling dates of the isolates, which extended from 1999 to 2016. The substitution rate estimated for the original dataset and for the 100 randomizations was compared to verify a lack of overlap between the 95% credible intervals Both lineage 4 and lineage 2 datasets showed a clear temporal signal (Supplementary Fig. 4), and model parameters could be confidently inferred from the data[30,31]. None of the drug resistant nodes reverted to susceptible along the branches of the two phylogenetic trees
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