Despite being curable, leprosy still persists in many developing countries, with more than 200,000 new cases every year and drug-resistant strains of the leprosy bacterium emerging.
To fight leprosy, scientists need to better understand the biology of Mycobacterium leprae, which has been difficult as the bacterium cannot be grown in a lab. Now, an international team of scientists from Ecole Polytechnique Federale de Lausanne has isolated, sequenced, and analyzed the genomes of 154 strains of M. leprae. The study, published in Nature Communications today, found several genes that are associated with resistance to antibiotics, including new genes that might point to previously unknown mechanisms of drug resistance.
"This is an important finding," says Stewart Cole, project leader. "The way clofazimine, one of the main leprosy drugs, works is completely unknown but now we have a new lead to investigate thanks to this analysis of multidrug-resistant M. leprae."
Isolating M. leprae DNA was a challenging task, as the amount of bacteria in skin biopsies is generally low and varies greatly between patients. The team had to develop methods to isolate and purify M. leprae DNA that enabled whole genome sequences to be obtained directly from human biopsy material, thus removing the necessity for passage through animals. Once the bacterium's DNA was isolated, the researchers were able to sequence it and compare it with that from other samples.
The scientists also found eight strains of M. leprae whose genomes harbored an incredibly large number of random mutations, accumulated over a period of a few years or perhaps decades. These eight strains are all resistant to multi-drug therapy, and were the only ones in the study in which a gene that is responsible for DNA repair is disrupted.
"It's a fascinating survival strategy against antibiotics," explains Andrej Benjak, the study's leading author. "Disrupting DNA repair will result in a storm of random mutations, increasing the chance that the right gene mutates at the right spot and lead to drug resistance. But random mutations can be deadly, so it's like a desperate, genetic Russian roulette for the bacterium."
The researchers also discovered that leprosy itself might have originated in the Far East. Several bacterial strains from East Asia belonged to the ancestral lineages of the leprosy bacilli. "People naturally assume that old human diseases originated in Africa, but for leprosy, the evidence points to Eurasia," says Charlotte Avanzi, one of the study's authors from Cole's lab.