Visceral leishmaniasis: an integrated review of resistance mechanisms, host immunometabolism, and next generation therapeutics.

Leishmania donovani is the most common cause of visceral leishmaniasis, which has been a significantly neglected tropical disease with high morbidity and mortality rates in the endemic countries. The persistence with a small number of antileishmanial drugs has led to the development and propagation of drug resistance, which undermines treatment efficacy and control initiatives. This review presents a multidisciplinary and in-depth analysis of the mechanisms of drug resistance in VL, integrating parasite-specific determinants with host-level metabolic reprogramming. We discuss the molecular mechanisms of drug neutralisation caused by dysregulation of drug uptake and efflux in aquaglyceroporin-1 (AQP1), as well as additional drug neutralisation caused by thiol-based redox detoxification in the trypanothione pathway. We also discuss the role of the parasite in manipulating host macrophage cholesterol dynamics, lipid raft disruption, and immune suppression to create a permissive intracellular niche that suppresses drug accumulation and drug response. The contribution of sterol remodelling, especially through the parasite-specific LdSMT enzyme and CYP710C1-mediated production of stigmasterol, is addressed in the context of both resistance acquisition and rational drug targeting. On the therapeutic side, the present article assesses the existing evidence base of combination regimens, host-directed approaches, and new oral pipeline of novel oral candidates, under clinical development by DNDi and partner institutions, such as LXE408, DNDI-6174, liposomal nanoformulations. Further, the article provides a survey of the topography of diagnostic instruments, including strong points and translational shortcomings of parasitological confirmation, molecular and serological. Together, this review highlights the necessity of combined, surveillance-based, and target-specific strategies in order to support and prolong the achieved progress in VL eradication.