Leprosy (Hansen disease) and Buruli ulcer are among the devastating skin neglected tropical diseases (Skin NTDs) prevalent in sub-Saharan Africa that cause progressive and permanent disabilities, exposing the patients and their families to discrimination, social stigma, and economic burden, adding complex challenges to communities already exposed to extreme inequality. Considering the needs of the most affected populations, children and people living in rural remote areas, current treatments are suboptimal in their complexity and length. Treating leprosy requires multiple drugs administered for 6 to 12 months. Buruli ulcer treatment requires 3 pills daily at different hours for two months, and lesion healing can take up to 12 months. Both treatments are associated with significant side effects (skin discoloration from clofazimine, exacerbating the stigma that leprosy patients face, and potentially fatal hypersensitivity to dapsone). This proposal aims to transform the treatment of Buruli ulcer and leprosy using the novel compound telacebec. Telacebec has demonstrated profound activity against Mycobacterium ulcerans and Mycobacterium leprae, the causative agents of Buruli ulcer and leprosy, respectively, whose evolutionary biology has rendered them hypersusceptible to killing by telacebec. We propose to conduct two clinical trials with telacebec-based treatment regimens that will cure Buruli ulcer and leprosy with fewer drugs, shorter duration, and fewer side effects than current therapy. We will perform this work through an integrated, multidisciplinary consortium of experts with broad experience in drug development, therapeutic delivery, community engagement, stakeholder participation, policy implementation, and capacity building to achieve equitable access to a new standard of care for these diseases.