About Authors
Jatin Malik1, Rafael Balana Fouce2, Chandra Sekhar Venkata Gowri Kondapalli3, Murugesan Sankaranarayanan*1
1Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Vidya Vihar, Pilani-333031, Rajasthan, India.
2Department of Biomedical Sciences, Faculty of Veterinary Medicine, University of Leon, Leon, Spain-24071.
3Department of Chemistry, Birla Institute of Technology and Science Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Hyderabad-500078, Telangana, India.
*Corresponding Author : E-mail: murugesan@pilani.bits-pilani.ac.in
Introduction
Leishmaniasis occupies a grim and persistent position among the world’s most consequential neglected tropical diseases (NTDs), afflicting millions of individuals across some of the most resource-limited regions in the world.1 It is caused by obligate intracellular protozoan parasites of the genus Leishmania, which belong to the order Trypanosomatida and the family Trypanosomatidae-a group phylogenetically unified by their characteristic kinetoplast, a specialized mass of mitochondrial DNA with no true mammalian counterpart. Today, leishmaniasis is classified by the World Health Organization (WHO) as one of the top-ten NTDs of global public health significance and is listed among the epidemic-prone diseases requiring intensified surveillance and international commitment.2 Despite decades of scientific inquiry, the disease continues to exact a devastating toll on human life, productivity, and socioeconomic development, particularly in regions where poverty, malnutrition, poor vector-control infrastructure, and inadequate access to healthcare converge to create conditions highly permissive for transmission.
Causative Agents and Transmission Biology
More than 20 Leishmania species are pathogenic to humans, and their transmission is mediated by the bite of infected female sandflies belonging to the genus Phlebotomus in the Old World (Eastern Hemisphere) and Lutzomyia in the New World (Western Hemisphere). Approximately 30 proven sandfly species serve as competent vectors, with the tiny 2-3 mm female insects acquiring the promastigote form of the parasite while taking a blood meal from an infected reservoir host, followed by its development and anterior migration within the insect midgut into the infective metacyclic promastigote stage, which is subsequently inoculated into a new vertebrate host during a subsequent feeding event. Upon deposition in dermal tissue, promastigotes are rapidly phagocytosed by host macrophages and dendritic cells, whereupon they differentiate into the non-flagellated amastigote form, which replicates within the phagolysosomal compartment of these professional antigen-presenting cells-an intracellular sanctuary that renders the parasite highly resistant to humoral immune responses (Fig. 1). The clinical outcome of infection is determined by a complex interplay of parasite species, inoculation site, host immune status, and vector biology.3
Fig. 1: Life cycle of Leishmanial parasite
Visceral leishmaniasis (VL), the most severe form, is caused predominantly by Leishmania donovani in South Asia and East Africa, and by Leishmania infantum in the Mediterranean basin, the Middle East, Central Asia, and Latin America. Cutaneous leishmaniasis (CL), the most prevalent form globally, arises from a broader array of species. Mucocutaneous leishmaniasis (MCL), characterized by destructive metastatic invasion of the nasopharyngeal mucosa, is caused chiefly by Leishmania braziliensis and is endemic in South America. Post-kala-azar dermal leishmaniasis (PKDL), a dermal sequela appearing weeks to months after apparently successful treatment of VL, represents an important epidemiological reservoir for ongoing anthroponotic transmission of L. donovani in the Indian subcontinent and East Africa.4 Zoonotic transmission, with dogs, rodents, and other mammals serving as reservoir hosts, predominates in most endemic settings, while the Indian subcontinent represents the classic anthroponotic focus in which humans themselves constitute the principal reservoir, rendering elimination theoretically achievable through aggressive case detection and treatment.
Global and Indian Epidemiology: WHO/DNDi Statistics and Mortality Burden
The global epidemiological footprint of leishmaniasis is staggering in scale and inequity. According to the WHO Global Health Observatory, leishmaniasis is currently endemic in 99 countries and territories spanning five continents, placing an estimated 310 million people at risk of infection, with 4-12 million individuals estimated to be living with active disease at any given time. The annual incidence comprises approximately 0.2-0.4 million new cases of VL and 0.7-1.2 million new cases of CL, representing a combined global burden that renders leishmaniasis the third most significant vector-borne parasitic disease in the world, surpassed only by malaria and lymphatic filariasis. As of November 2025, data reported to the WHO Global Leishmaniasis programme for 2024 revealed that approximately 85% of global VL cases were concentrated in just seven countries: Brazil, Ethiopia, India, Kenya, Somalia, South Sudan, and Sudan-a geographic clustering that starkly reflects the interplay between poverty, ecological determinants of sandfly habitat, and inadequacies in public health infrastructure (Fig. 2). For CL, seven countries-Afghanistan, Algeria, Brazil, Colombia, Iran, Peru, and the Syrian Arab Republic-collectively accounted for 83% of global reported incidence in 2024.5
Fig. 2 : Global distribution and epidemiological statistics of leishmaniasis
Clinical Manifestations of Kala-Azar
Visceral leishmaniasis (VL), commonly known as kala-azar, derives its name from the Hindi and Bengali words meaning “black fever” and represents the most severe manifestation of leishmaniasis. The disease is characterized by an insidious onset and a systemic course, with an incubation period ranging from weeks to months. During this period, Leishmanial parasites disseminate silently from the site of inoculation in the skin to the reticuloendothelial system, colonizing the spleen, liver, bone marrow, and lymph nodes (Fig. 3). The classical clinical triad of VL comprises prolonged irregular fever, progressive weight loss and wasting, and marked splenomegaly, often accompanied by hepatomegaly.6
If left untreated, VL is almost invariably fatal, with case-fatality rates exceeding 95%. The disease is particularly aggressive in immunocompromised individuals, especially those co-infected with HIV, where frequent relapses and high mortality are common. An important post-treatment complication is post-kala-azar dermal leishmaniasis (PKDL), characterized by macular, papular, or nodular skin lesions that may appear months to years after apparent cure. PKDL patients often remain infectious to sandflies and therefore constitute an important reservoir sustaining disease transmission and challenging elimination efforts.7
Fig. 3: Clinical manifestations of leishmaniasis
Treatment Strategies: Approved Drugs, Regimens, and Economic Dimensions
Current chemotherapy for VL remains limited to a few approved drugs, each associated with significant drawbacks related to toxicity, cost, administration, or emerging resistance (Fig. 4). Pentavalent antimonials, including sodium stibogluconate and meglumine antimoniate, were the mainstay of VL treatment for decades and continue to exhibit efficacy in East Africa and Latin America. Their prolonged parenteral administration and severe toxicities, including cardiotoxicity and pancreatitis, further restrict their use. Liposomal amphotericin B (L-AmB; AmBisome) is currently the preferred, achieving cure rates of 90-95% with single-dose regimens and contributing substantially to kala-azar elimination efforts.8 Nevertheless, its high cost, intravenous administration, cold-chain requirements, and nephrotoxicity limit accessibility in resource-poor settings. Miltefosine, the first oral antileishmanial agent, revolutionized VL treatment with cure rates exceeding 94%; however, teratogenicity, gastrointestinal adverse effects, and increasing resistance threaten its long-term utility. Paromomycin, an aminoglycoside antibiotic, offers an affordable alternative and exhibits high efficacy, particularly in combination regimens.9 Consequently, WHO now recommends combination therapies, such as single-dose L-AmB with miltefosine or paromomycin, which shorten the treatment duration, improve adherence, and potentially delay the emergence of resistance.
Fig. 4: Structure of current treatment and clinical trial molecules against Leishmaniasis
Clinical Trial Pipeline: Emerging Molecular Entities and Investigational Approaches
The clinical pipeline for leishmaniasis, while significantly more populated than a decade ago, remains critically underdeveloped relative to the disease burden. Drugs for Neglected Diseases initiative (DNDi), the nonprofit product development partnership that has assumed global leadership in antileishmanial drug development, currently maintains a portfolio of new chemical entities (NCEs) spanning early discovery to early clinical development. DNDI-6899, a cyclin-dependent kinase 12 (CRK12) inhibitor developed in collaboration with GlaxoSmithKline, is currently under of Phase I clinical trial.10 LXE408, a proteasome inhibitor co-developed by Novartis, has demonstrated excellent potency against L. donovani in vitro and in vivo and has progressed through Phase I safety evaluation, providing important proof-of-concept for target-based therapeutics against this pathogen (Fig. 5). DNDI-6148, a benzoxaborole derivative that targets the mRNA cleavage and polyadenylation specificity factor (CPSF) of Leishmania, a mechanism validated by its structural analog AN2690 (tavaborole) in fungal pathogens, achieved greater than 98% parasite burden reduction in murine VL models and is advancing through preclinical development. DNDI-0690 and DNDI-2319 represent further chemical series at early clinical or late preclinical stages.11
Fig. 5 : Structure of DNDi pipeline candidates against Leishmaniasis
Challenges in Leishmaniasis Treatment: A Multidimensional Crisis
The challenges confronting leishmaniasis drug development and treatment delivery are deeply intertwined across biological, economic, and systemic dimensions that no single intervention can resolve in isolation. From a pharmacological standpoint, the efficacy of existing treatments may drop to as low as 50% in certain geographic contexts and Leishmania species combinations, and there is currently no universal antileishmanial treatment regimen that performs adequately across all clinical forms and endemic regions. Drug resistance represents a particularly acute and evolving threat: antimony resistance in India has been followed by emerging miltefosine treatment failures attributable to both pharmacokinetic underdosing and parasite-intrinsic resistance mechanisms including loss-of-function mutations in the miltefosine transporter. The obligate intracellular biology of Leishmania creates a formidable pharmacokinetic challenge, requiring drugs to achieve sufficient macrophage penetration and intraphagolysosomal concentration to kill amastigotes within a compartment evolved to destroy foreign molecules.12 All currently approved small-molecule antileishmanial agents are effectively repurposed drugs originally developed for oncology, infectious diseases, or other indications, none were de novo designed against a Leishmania-specific molecular target-and their toxicity profiles reflect this non-specificity (Fig. 6).
The entire antileishmanial drug development enterprise suffers from a chronic market failure rooted in the economic characteristics of the patient population: leishmaniasis predominantly affects the rural poor in low-income countries, who lack purchasing power to sustain a commercial market capable of recouping pharmaceutical industry research and development investments, which can exceed $1–2 billion per approved drug under conventional development models. An analysis by the Lancet revealed that between 2000 and 2011, less than 1% of new drugs and vaccines approved globally were indicated for NTDs-a disproportion that fundamentally reflects the misalignment between global disease burden and commercial pharmaceutical incentives.13 The absence of an approved human vaccine, despite decades of research into Leishmania immunobiology and the demonstrated feasibility of vaccine-induced protection in animal models, represents a critical gap that continues to increase the burden on therapeutic interventions.
Fig. 6: Limitations of approved antileishmanial therapies
Future Directions and the Strategic Imperative
The path forward for leishmaniasis drug discovery demands a fundamental paradigm shift from empirical, phenotype-driven approaches toward rigorously target-based medicinal chemistry programs anchored in a deep mechanistic understanding of parasite biology. Among the most compelling validated molecular targets in Leishmaniasis is trypanothione reductase (TryR), an NADPH-dependent flavoenzyme that is absolutely essential for maintaining the parasite’s unique thiol-redox homeostasis present exclusively in trypanosomatids and absent in mammalian cells. Fragment-based drug discovery (FBDD), structure-based virtual screening (VS), and covalent warhead approaches are being applied to TryR with increasing sophistication. CRK12 kinase, the proteasome, CPSF mRNA-processing machinery, and the ergosterol biosynthetic pathway each represent additional target classes where the combination of parasite essentiality, structural divergence from host orthologs, and emerging small-molecule validation data provides a compelling case for sustained medicinal chemistry investment.
A critical strategic need is the deepening of academia-industry collaboration through non-conventional models that deconflict the inherent tension between commercial pharmaceutical imperatives and neglected disease drug development. The DNDi model of a nonprofit product development partnership that aggregates public, philanthropic, and industry funding, leverages academic and industrial research assets under open-access IP frameworks, and coordinates global clinical trial networks in endemic countries has proven catalytic but insufficiently resourced to address the full scope of the pipeline gap. Initiatives such as the Global Health Innovative Technology (GHIT) Fund, operating through Japan-based public-private partnerships, and the Wellcome Trust’s commitment to neglected disease research represent important complementary funding mechanisms, but the aggregate annual global investment in leishmaniasis R&D-estimated at approximately $50–70 million-remains orders of magnitude below what is required to advance multiple NCEs through the full clinical development pathway simultaneously.
In conclusion, leishmaniasis continues to impose an unacceptable human cost upon the world’s most marginalized communities, and the existing therapeutic arsenal is woefully insufficient. The global leishmaniasis community urgently requires a substantial and sustained increase in funding for target-validated drug discovery programs, particularly those employing structure-based drug design (SBDD) against parasite-specific enzyme, a re-architecting of academia-industry partnerships through open-innovation and risk-sharing frameworks that align commercial and public health incentives; expanded regulatory support in the form of adaptive trial designs and streamlined approval pathways in endemic countries.
Conflicts of Interest
There are no conflicts of interest to declare.
Acknowledgements
We sincerely express our gratitude to BITS-Pilani, Pilani Campus, and BITS-Pilani, Hyderabad Campus, for providing the necessary facilities to do the work. The authors SM and KVGC acknowledge the funding received from the SERB-CRG projects (Ref. No. CRG/2022/005290 and CRG/2022/001889) under the Department of Science and Technology (DST), New Delhi.
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