Unraveling Drug Resistance in Mycobacterium leprae: Exploring Genetic Mutations to Enhance Treatment Strategies for Human Leprosy-A Narrative Review.

Leprosy, one of the oldest diseases, is caused by Mycobacterium leprae and Mycobacterium lepromatosis and continues to pose a significant global public health challenge despite decades of control efforts and the widespread use of multidrug therapy. Clinical manifestations range from tuberculoid to severe lepromatous forms, often accompanied by immune-mediated inflammatory reactions. The disease exhibits a long incubation period, high infectivity, and complex immune-mediated pathology, complicating timely diagnosis and management. Although multidrug therapy comprising rifampicin, dapsone, and clofazimine remains the mainstay treatment recommended by the World Health Organization for leprosy and has proven to be highly effective in managing both multibacillary and paucibacillary forms, the treatment outcomes are hindered by drug resistance, adverse drug reactions, and poor adherence. Resistance primarily arises from genetic mutations in drug target genes such as rpoB, folP1, and gyrA, with additional contributions from efflux mechanisms and cell wall impermeability. This narrative review draws upon a comprehensive search of electronic databases to enhance understanding of the genetic mutations associated with drug resistance. It further highlights ongoing research into resistance mechanisms, novel therapeutic options, postexposure prophylaxis, and vaccine development, which are critical for sustaining the effectiveness of multidrug therapy and advancing global leprosy control efforts.