Innovative Therapies for Leishmania Infections: From Novel Compounds to Natural Product Inhibitors

Leishmaniasis remains a major neglected tropical disease in humans, driven by diverse Leishmania species transmitted by sand flies and shaped by complex interactions between parasite, host, and environment. Human infections range from asymptomatic carriage to severe visceral disease, cutaneous and mucocutaneous, often occurring in regions with limited access to effective therapeutics, diagnostics, and vector control. Limitations of current drugs—including toxicity, long treatment regimens, high cost, and emerging resistance—underscore the urgent need for innovative therapies. Within the scope of infectious agents and disease, Leishmania provides a powerful model for discovering and validating novel anti-infective strategies, spanning small molecules, biologics, host-directed interventions, and natural product–derived compounds with direct relevance to global health.This article collection will spotlight advances in therapeutic discovery and development for human leishmaniasis. By integrating studies on anti-leishmania compound discovery and development with investigations of parasite pathogenicity, this topic highlights how targeting key virulence factors, survival pathways, and host–pathogen interactions can yield therapies that not only clear infection but also mitigate disease severity and progression. Particular emphasis will be placed on the identification, optimization, and mechanistic characterization of natural products and their derivatives as Leishmania inhibitors, alongside synthetic molecules, biologics, and drug repurposing strategies. By bringing together work that spans target discovery, hit-to-lead development, pharmacology, resistance mechanisms, and translational studies, this collection aims to accelerate the pipeline of safe, effective, and sustainable therapies against human Leishmania infections.The exploration of Leishmania pathogenesis inhibition includes but is not limited to the following areas.• Structural and functional analyses of drug targets such as pteridine reductase 1 and other essential enzymes or pathways in human-infective Leishmania species• Discovery, optimization, and mode-of-action studies of innovative synthetic compounds with anti-Leishmania activity• Identification, isolation, and characterization of natural products and natural product–inspired derivatives as Leishmania inhibitors• Preclinical evaluation of novel therapeutic candidates, including in vitro and in vivo efficacy, pharmacokinetics, and toxicity profiling• Drug repurposing and rational combination therapies to improve efficacy, reduce treatment duration, and overcome resistance in human leishmaniasis• Host-directed therapies that modulate immune or metabolic pathways to enhance control or clearance of Leishmania• Studies on mechanisms of drug resistance, tolerance, and persistence, and their implications for therapeutic design• Omics-based approaches (genomics, transcriptomics, proteomics, metabolomics) to identify new therapeutic targets and resistance markers• Methodological and technological advances that support anti-leishmanial drug discovery, such as high-throughput screening platforms or novel in vitro/in vivo models Topic editors: Rakesh K. Singh, Namrata Anand Source: https://www.frontiersin.org/research-topics/76611/innovative-therapies-for-leishmania-infections-from-novel-compounds-to-natural-product-inhibitors