Abstract
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.
Highlights
Leprosy is a chronic human disease caused by the yet-uncultured pathogen Mycobacterium leprae
The DNA extraction method used in this study was applied directly to punch biopsies from clinically well-characterized patients of known bacillary index (BI) and exploits the fact that M. leprae resides intracellularly
There was a direct correlation between genome coverage and the BI but, surprisingly, successful coverage could even be achieved with some specimens whose BI was as low as 1+
Summary
Leprosy is a chronic human disease caused by the yet-uncultured pathogen Mycobacterium leprae. We develop and apply methods to isolate and purify M. leprae DNA that enable whole genome sequences to be obtained directly from human biopsy material, removing the necessity for passage through animals. This approach was successfully used to generate 120 new M. leprae genome sequences from drug-susceptible and DR strains from around the world, thereby enabling detailed phylogenetic and phylogeographic comparisons to be performed, new mutations associated with antimicrobial resistance to be detected, and the likely origin of leprosy to be proposed
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