Genomic Analysis Finds Genes Associated with Antibiotic-Resistant Leprosy

Researchers report that they have isolated, sequenced, and analyzed the genomes of Mycobacterium leprae from around the world. The study found several genes that are associated with resistance to antibiotics, including new genes that might point to previously unknown mechanisms of drug resistance.

Despite being curable with multidrug therapy, leprosy still persists in many developing countries, with more than 200,000 new cases every year and increasing drug-resistant strains of the leprosy bacterium emerging, according to the scientists, who published their study (“Phylogenomics and Antimicrobial Resistance of the Leprosy Bacillus Mycobacterium leprae”) in Nature Communications.

“Leprosy is a chronic human disease caused by the yet-uncultured pathogen Mycobacterium leprae….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 [multidrug therapy]-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,” write the investigators.

“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.”

To overcome antibiotic resistance, scientists need to better understand the biology of M. leprae and specifically how it interacts with its host. However, studying the bacterium is difficult, as it cannot be grown in a lab.

“This is an important finding,” says Stewart Cole, a Ph.D., who heads his own lab at the Global Health Institute, École Polytechnique Fédérale de Lausanne (EPFL). “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.”

The scientists also found eight strains of M. leprae whose genomes harbored a large number of random mutations, accumulated over a period of a few years or perhaps decades. These eight strains are all resistant to multidrug 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, Dr. rer. na., EPFL, 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 leads 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, Pharm.D., one of the study's authors from Dr. Cole's lab.

Narrowing down the location of the origin will facilitate the reconstruction of the spread of the disease. “We need more samples from Central Asia and the Middle East, but these are hard to get due to current geopolitical issues,” says Avanzi. “For Europe, where leprosy is eradicated, we have to rely on ancient human remains. But it's possible—we have developed the tools, and now we are ready to sequence even more samples.”