DNA repair pathways in Mycobacterium leprae: insights from reductive genome evolution and therapeutic opportunities

DNA repair mechanisms are critical for shielding the bacterial genome from damage induced by various stressors. The survival of Mycobacterium leprae, the causative agent of leprosy, within the human host is also closely linked to the maintenance of its genomic integrity and requires the coordinated action of multiple DNA repair pathways. However, the M. leprae genome is characterised by extensive reductive evolution, retaining only 49.5% functional gene content. A total of 61 genes related to DNA repair pathways have been identified in M. leprae, comprising 36 encoding well-annotated functional proteins, 11 encoding hypothetical proteins, and 14 pseudogenes. Many of these DNA repair genes exhibit homology to counterparts found in Escherichia coli and Mycobacterium tuberculosis. Notably, several of these functional genes encode hypothetical proteins whose exact functions remain uncharacterised. Several hypothetical proteins identified through comparative genomic analyses are predicted to participate in DNA repair pathways, although their functions remain experimentally unvalidated. These proteins may complement the conserved DNA repair machinery and contribute to the long-term survival and persistence of M. leprae within the host. Targeting them may impede pathways and improve host-mediated clearance. Given their potential roles in bacterial survival and pathogenesis, these components of the DNA repair system represent a promising therapeutic target. Thus, gaining deeper insight into how DNA repair pathways contribute to Mycobacterium pathogenesis could reveal future opportunities for effective leprosy treatment. This review provides a comprehensive overview of DNA repair pathways in M. leprae and highlights their potential as a therapeutic intervention.