| Sumario: | Leprosy is a chronic human disease caused by the yet-uncultured pathogen Mycobacterium leprae.
Although readily curable with multidrug therapy (MDT), over 200,000 new cases are still
reported annually. Here, we obtain M. leprae genome sequences from DNA extracted directly from
patients’ skin biopsies using a customized protocol. Comparative and phylogenetic analysis of 154
genomes from 25 countries provides insight into evolution and antimicrobial resistance, uncovering lineages and phylogeographic trends, with the most ancestral strains linked to the Far East.
In addition to known MDT-resistance mutations, we detect other mutations associated with
antibiotic resistance, and retrace a potential stepwise emergence of extensive drug resistance in
the pre-MDT era. Some of the previously undescribed mutations occur in genes that are apparently subject to positive selection, and two of these (ribD, fadD9) are restricted to drug-resistant
strains. Finally, nonsense mutations in the nth excision repair gene are associated with greater
sequence diversity and drug resistance.
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