Beyond resistance: Emerging methods to dissect drug responses in Leishmania

Treatment failure and relapse remain major challenges in leishmaniasis despite available chemotherapies. Historically, these outcomes have been interpreted through the lens of classical drug resistance driven by heritable genetic mutations. However, drug responses are increasingly recognised to extend beyond resistance and include distinct but related phenomena such as hypersensitivity, tolerance, and persistence. Dissecting this range of responses in Leishmania requires approaches that capture both heritable genetic variation and dynamic cellular states. Here, we highlight how emerging genomics and perturb-omics technologies can resolve mechanisms underlying diverse drug responses. We emphasise that their impact depends on state-aware experimental design, including calibrated drug-selection, varied exposure regimens, and strategies to isolate rare persister populations. Together, these approaches provide a framework to move beyond resistance-centric models towards a more comprehensive understanding of parasite drug response.