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All issues Volume 32 (2025) Parasite, 32 (2025) 18 Full HTML
Open Access
Review
Issue
Parasite
Volume 32, 2025
Article Number 18
Number of page(s) 17
DOI https://doi.org/10.1051/parasite/2025009
Published online 05 March 2025

© A. Majoor et al., published by EDP Sciences, 2025

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

Leishmaniasis, a vector-borne disease transmitted through the bite of phlebotomine sand flies, poses a threat to more than 1 billion people in over 98 countries worldwide [111]. It is responsible for 20,000 to 30,000 deaths a year and has been considered an uncontrolled neglected tropical disease by the World Health Organization (WHO) since 2011 [111].

Leishmania parasites exhibit a preference for the reticulohistiocytic system in mammals, with macrophages serving as their primary host cells. Inside these cells, the parasite replicates until the macrophage ruptures, enabling the infection to spread. Over 20 species of Leishmania are known to cause disease, each exhibiting distinct tropisms that lead to outcomes ranging from asymptomatic carriage to diverse clinical manifestations. These manifestations range from self-healing skin ulcers to systemic infections characterized by hepatosplenomegaly, which can be fatal if left untreated.

Human leishmaniasis manifests in four main forms. The most common form, cutaneous leishmaniasis, causes ulcerative skin lesions and is typically associated with Leishmania (L.) major, L. tropica, or L. mexicana. Muco-cutaneous leishmaniasis (MCL) caused by L. braziliensis, L. panamensis, and L. amazonensis affects the mucous membranes of the nose and mouth, resulting in severe disfigurement as the disease progresses. Visceral leishmaniasis, the most severe form of the disease, primarily targets the liver and spleen, causing irregular fever and severe hepatosplenomegaly, with a mortality rate of 95% if left untreated. It is predominantly caused by L. donovani, which can also lead to post-kala-azar dermal leishmaniasis, a condition marked by widespread skin lesions that appear after an initial cure of visceral leishmaniasis [90]. Leishmania infantum is another species associated with visceral leishmaniasis.

The disease caused by L. infantum primarily affects dogs, which serve as the reservoir for this parasite. Non-infected sand flies can acquire the parasite during a blood meal from an infected dog and subsequently transmit it to other mammals, such as foxes, rodents, and humans. In dogs, clinical symptoms often begin with skin-related issues, such as alopecia, onychogryphosis, and eye problems including keratoconjunctivitis and uveitis. If untreated, these symptoms can progress to a visceral form, characterized by splenomegaly, kidney failure, weight loss, muscle wasting, and lethargy [77].

Currently, two vaccines are available for canine leishmaniasis caused by L. infantum: LetiFend® in Europe, and Leish-Tec® in Brazil [50]. However, no effective vaccine exists for humans [106]. Prevention in humans relies entirely on avoiding sand fly bites through the use of repellents, insecticide sprays, or mosquito nets. Once an infection occurs, treatment remains the only option. Pentavalent antimonials are commonly used as the first-line treatment in most countries. However, increasing drug resistance has become a major concern [36]. Nowadays, liposomal amphotericin B (L-AMB) is considered as the first-line treatment in high-income countries [80]. Despite their efficacy, existing treatments have significant limitations, including invasive administration, long treatment durations, high costs, and the emergence of resistance [75].

Given these challenges, there is an urgent need to develop novel alternative treatments. In this review, we discuss the limitations of current therapies and propose strategies to address these issues. Specifically, we focus on reducing toxicity, costs, and resistance, while exploring new administration routes and methods to shorten treatment durations.

Materials and methods

This review concentrated on studies conducted in vivo and in vitro on amastigotes, as these are the intracellular forms responsible for the disease. Screening on promastigotes was excluded because, although amastigote-based screening offers a high hit-to-success ratio, promastigote-based screening often fails during later stages of drug development [23]. This review highlights strategies for developing treatments against leishmaniasis, focusing on progress made between 2015 and 2023. Bibliographic research was conducted on PubMed using keywords such as leishmaniasis, treatment, cutaneous or mucocutaneous or visceral, mechanism, and combination. Over 600 articles matching these keywords were identified and categorized based on the drug development strategy they addressed. First, we reviewed current therapies validated for treating Leishmania, along with their mechanism of action and limitations. Combination therapies were then explored, emphasizing the simultaneous use of several approved compounds. We also examined two key strategies responsible for more than half of the major approved treatments: nanoparticle carriers, as seen with liposomal amphotericin B, and drug repositioning exemplified by miltefosine and paromomycin. Additionally, we investigated articles on immunotherapy with current treatments and studies on ethnobotanics as a strategy for novel drug discovery.

Results

Current treatment options and limitations

Currently, seven approved treatments are used against different forms of leishmaniasis worldwide (Table 1). Historically (Fig. 1), the first approved treatment, based on trivalent antimonials, was introduced in 1912. By 1922, these were replaced by safer pentavalent antimonials, leading to the development of today’s two approved molecules: sodium stibogluconate (SSG) and meglumine antimoniate. These drugs were highly effective until the 1970s and 1980s, when significant treatment failures and the emergence of resistant strains began to be observed [110]. Despite their efficacy, they are associated with side effects such as gastrointestinal issues (vomiting, anorexia) and cardiotoxicity. Pentamidine, approved in the 1940s, is another drug used to treat leishmaniasis. However, its use has been restricted by the WHO due to severe side effects, including diabetes mellitus, severe hypoglycemia, shock, and myocarditis. Ketoconazole and fluconazole, discovered in 1977 and 1978, respectively are treatment options for cutaneous leishmaniasis [110]. However, the development of resistance in Leishmania parasites has limited their effectiveness. In 1996, the approval of amphotericin B (AMB) addressed some resistance issues, but this drug is associated with side effects such as fever, chills, rigor, and nephrotoxicity. In 1999, L-AMB was developed to reduce toxicity. While liposomal encapsulation improved safety, it significantly increased the cost, making it less accessible in developing countries [12]. Until 2004, all treatments for visceral leishmaniasis required invasive administration via the intravenous or intramuscular routes. This made treatment difficult in some regions, where multiple hospital visits were required for injections. The approval of miltefosine in 2004 marked a breakthrough as the first oral drug for leishmaniasis. Despite its advantages, miltefosine is teratogenic, limiting its use in pregnant women, and causes gastrointestinal side effects [12]. Paromomycin, an aminoside antibiotic, became the most recent anti-leishmanial drug approved in 2006 [16, 86]. However, its use is limited due to side effects, including ototoxicity, renal toxicity, and hepatotoxicity.

thumbnail Figure 1

Current treatments and their development over time.

Table 1

Classical monotherapies used for Leishmania infection.

Today, these drugs (Table 1) remain the first-line treatments recommended by WHO guidelines for all forms of leishmaniasis. Despite their efficacy, they have significant limitations. Most treatments require invasive administration, have long treatment durations, and are associated with high costs and toxicity. Additionally, treatment failures are becoming more frequent, and resistant Leishmania isolates are increasingly reported for all approved regimens [75].

Combination therapies

Combination therapy is a promising strategy to address the limitations of current anti-leishmanial drugs. By combining two treatments with complementary or distinct mechanisms of action, this approach seeks to enhance therapeutic efficacy and potentially achieve synergistic effects. Targeting different biological pathways or stages of the parasite’s lifecycle also reduces the likelihood of developing drug resistance. For instance, Mutiso et al. demonstrated the effectiveness of combining diminazene and artesunate—two drugs with distinct mechanisms of action against L. donovani in a mouse model [66]. This combination was more effective than either drug alone, highlighting the potential for synergistic effects. It also reduced drug doses, lowering toxicity and treatment costs, particularly for expensive therapies like L-AMB [66].

Several drug combinations have been tested with success, significantly reducing treatment durations (Tables 2 and 3). In humans, the combination of 20 mg/kg SSG and 15 mg/kg paromomycin reduced treatment time from 30 days to 17 days, maintaining the same efficacy. In India, combining L-AMB with 50–100 mg/kg miltefosine or 11 mg/kg paromomycin shortened treatment duration from 31 to 7–10 days. It also reduced the L-AMB dose from 15 mg/kg over 30 days to a single 5 mg/kg injection, decreasing cost and toxicity [38, 88]. To select an appropriate treatment, one approach is to align with the WHO recommendations [110, 112]. For HIV-positive patients, a combination of 30 mg/kg L-AMB and 100 mg/day miltefosine over 25 days increased cure rates from 50% with L-AMB monotherapy (40 mg/kg) to 81% [105, 112].

Table 2

Combination therapies for human leishmaniases.

Table 3

Combination therapies for canine leishmaniases.

In dogs, reference treatment is a combination therapy of 100 mg/kg/day meglumine antimoniate and allopurinol or miltefosine and allopurinol [50]. Miltefosine promotes remission by sustaining the inflammatory environment harmful to the parasite [84]. However, Manna et al. reported fewer relapses with meglumine antimoniate and allopurinol compared to miltefosine alone [54]. Paromomycin showed safety in dogs, but did not significantly improve cure rates compared to the reference treatment [44].

Experimental treatments in hamsters have explored topical applications of paromomycin for cutaneous leishmaniasis in combination with meglumine antimoniate (Glucantime®) or miltefosine. These combinations, even at suboptimal doses, were more effective than monotherapy, suggesting that topical paromomycin may be a viable option for reducing parasite load [60]. Combining miltefosine and paromomycin also showed enhanced efficacy, with no observed cross-resistance development upon repeated exposure [42].

While combination therapies can improve efficacy, reduce toxicity, and lower costs, they are not always successful [8, 93, 109]. Risks include the potential amplification of the side effects of both treatments and the potential development of drug resistance. For example, L. donovani has shown resistance to certain drug combinations in vitro, as reported by García-Hernández et al. [31]. These findings highlight the need for careful monitoring and the strategic use of combination therapies to mitigate the risk of resistance. In addition to combination therapies, other strategies, such as improving drug delivery systems using nanoparticles, have shown promise. Encapsulation of anti-leishmanial treatments, such as amphotericin B, has demonstrated potential to enhance efficacy and reduce limitations.

Nanoparticle carriers

Nanoparticles are small assemblies of organic or inorganic matter, sized between 1 and 100 nm, that offer significant potential in drug delivery. Organic nanoparticles can be classified into two main subgroups: polymeric nanoparticles, such as dendrimers, and lipid-based nanoparticles, such as liposomes. Lipid-based nanoparticles, primarily composed of phospholipids, are highly biocompatible and assemble into bilayered structures due to their amphipathic properties. These structures have a hydrophobic layer and a hydrophilic interior, enabling the solubilization and delivery of both hydrophilic and hydrophobic drugs. Among nanoparticle types, liposomes are the most commonly FDA-approved for clinical use. Polymeric nanoparticles offer greater structural variability due to their customizable compositions, allowing for the insertion of compounds to target specific intracellular sites [59]. Nanoparticles have largely been studied to improve the efficacy of anti-cancer drugs [115]. In anti-leishmanial therapy, liposomes have already demonstrated effectiveness, as amphotericin B is clinically administered in its liposomal form. Beyond liposomal formulations, several approved anti-leishmanial treatments have been encapsulated in various nanoparticles and tested in experimental models, such as mice and hamsters, to improve drug efficacy (Tables 4 and 5). Encapsulating approved treatments in lipid-based nanoparticles, such as liposomes, enhances drug stability and protects them from degradation in harsh environments, such as gastrointestinal fluids [29]. This allows for oral administration of drugs such as AMB [76], paromomycin [2], and pentamidine [102]. Additionally, nanoparticles enable topical administration of AMB, meglumine antimoniate, miltefosine [100], and SSG [20]. Liposomal formulations provide controlled drug release, extending the drug’s half-life and reducing peak concentrations, thereby lowering toxicity, particularly on renal function. Liposomes, being lipid-based, naturally interact with macrophage-rich organs such as the liver and spleen, improving bioavailability while minimizing systemic toxicity [89]. Nanoparticles can be functionalized with targeting groups to direct drugs to specific cells or organs. For example, phosphatidylserine signals macrophages, targeting the liver and spleen [89], lactoferrin interacts with C-type lectin receptors on antigen-presenting cells [6], guar gum targets mannose-like receptors on macrophages [76] and chitosan promotes phagocytosis, favoring liver and spleen targeting [101].

Table 4

Nanoparticle carriers with amphotericin B.

Table 5

Nanoparticle carriers with miltefosine, pentamidine or SSG.

Polymeric structures like dendrimers significantly increase the solubility of hydrophobic compounds. For instance, dendrimer formulations increased amphotericin B solubility by 478-fold using an anionic linear globular dendrimer carrier [32]. Some nanoparticles have immunomodulatory properties. Stearylamine-based lipid nanoparticles without any drug increased anti-leishmanial activity by promoting a Th1 immune response, upregulating IL-12, IFN-γ, and TNF-α, and activating iNOS pathways [5]. Similarly, compounds like lactoferrin and guar gum can activate macrophages, stimulating innate immune responses [40, 76].

In addition to encapsulating approved treatments, drug repositioning remains a viable strategy for addressing leishmaniasis. Repositioned drugs, such as amphotericin B, miltefosine, and paromomycin are already used as first-line treatments in many countries.

Drug repositioning

Approximately 60% of currently approved anti-leishmanial drugs are derived from the repositioning of existing medications initially developed for diseases other than leishmaniasis [12].

The most prominent class of repositioned drugs includes antimicrobial compounds (Table 6). For instance, amphotericin B is an anti-fungal that has been successfully repositioned for visceral leishmaniasis. Other anti-fungals, such as ketoconazole, fluconazole, and itraconazole, are recommended by WHO for cutaneous leishmaniasis [110]. These drugs target the ergosterol pathway, which is essential for the cell membranes of Leishmania, offering high selectivity without affecting mammalian cells. Promising candidates like butenafine, ravuconazole, and miconazole have also demonstrated their efficacy [3, 9, 99]. Paromomycin, an antibiotic belonging to the aminoglycoside class, can be used for cutaneous leishmaniasis (CL) as a topical treatment. Clinical trials showed that paromomycin cream achieved cure rates close to 80%, providing a non-invasive and effective alternative for CL [92]. Similarly, delamanid and SQ109, originally developed for tuberculosis have shown efficacy against L. donovani. Delamanid offers the added advantage of oral administration [33, 74].

Table 6

Repositioned drugs and their mechanisms of action.

Other antimicrobial repositioned drugs, such as fexinidazole and suramin, target metabolic pathways in Leishmania. Fexinidazole showed efficacy comparable to approved drugs. Indeed, 200 mg/kg of fexinidazole showed activity similar to the approved drugs miltefosine and SSG (Pentostam®). Suramin, with its immunomodulatory properties, reduced parasite burden in a mouse model infected by L. donovani [46, 74].

Anti-cancer drugs like miltefosine, ibrutinib, and imiquimod enhance host-mediated responses, particularly pro-inflammatory cytokine production [27, 103]. Miransertib and AR-12 reduced parasite burdens in vivo. Surprisingly, anti-depressants like sertraline and clomipramine have also shown potential by disrupting parasite mitochondrial functions and metabolic pathways. These drugs induced oxidative stress, ATP depletion, and apoptosis in Leishmania [52, 87].

Cholesterol reducer simvastatin boosts host defense by enhancing phagosome maturation, while rapamycin biases immune responses toward protective Th1 cytokines. The anti-arrhythmic drug amiodarone disrupts calcium homeostasis and sterol biosynthesis in Leishmania parasites [46, 71, 72].

Repositioning drugs not only leverages existing treatments, but also provides faster and more cost-effective solutions for combating leishmaniasis. However, to date, most assays using repositioned drugs against Leishmania have been conducted in vitro, with some also tested in mouse models. Many steps remain before these drugs can be used to treat patients. Combining immunomodulators with conventional treatments could further enhance their efficacy (Table 6).

Immunotherapies

Over the last 20 years, immunotherapy has been developed either as monotherapy or in combination with classically used treatments for leishmaniasis (Fig. 2). Immunity plays a critical role in the progression and outcome of the disease. Generally, Th1 immune responses involving IL-12, IL-18, IFN-g, and TNF-a are considered protective cytokines in Leishmania infections. Conversely, Th2 responses dominated by IL-4, IL-10, IL-13, and TGF-b favored parasite survival and disease progression [108]. For many years, research on leishmaniasis revolved around this Th1/Th2 dichotomy. However, it is now accepted that controlling Leishmania efficiently requires coordinated action of both pathways. Additionally, susceptibility to leishmaniasis depends on both host immunity and the virulence of the parasite species [38]. Combining current treatments with immunotherapy could reduce the concentration and duration of treatments for leishmaniasis, while shifting host immunity to favor Leishmania control.

thumbnail Figure 2

Immunochemotherapy tested in combination with drugs against Leishmania [9, 13, 35, 47, 53, 58, 63, 66, 85, 98, 107].

Since Th1 responses are protective against Leishmania infections, the first strategy used to enhance approved treatments has been to stimulate associated cytokines to favor remission. In dog models, domperidone and IFN-γ favor Th1 immune response and demonstrated activities against Leishmania. Domperidone is used for both prevention and treatment of canine leishmaniasis due to L. infantum [9]. Additionally, combining Glucantime® with IFN-γ has been shown to improve cure rates and reduce treatment duration, whereas Glucantime® plus active hexose correlated compound (AHCC) reduced adverse effects caused by allopurinol [9]. In mice, administering IL-12 with AMB increased the efficacy of a 2 mg/kg dose to match that of a 15 mg/kg dose [64].

Agonists of toll-like receptors (TLRs) have also been proposed. These receptors recognize pathogen-associated molecular patterns (PAMPs) [68] and trigger cytokine release via NF-κB activation, promoting pro-inflammatory responses. For example, the TLR-7 agonist imiquimod increased the efficacy of Glucantime® against L. major [98]. Similarly, the TLR-2 agonist Pam3Cys enhanced the efficacy of suboptimal doses of oral miltefosine against L. donovani in a mouse model [9].

Another strategy involves inhibiting Th2 responses by modulating cytokines. In mice, anti-IL-10R treatment accelerated L. donovani elimination and increased efficacy when combined with either Pentostam® or AMB [63–65].

In humans, the combination of IFN-γ with L-AMB has proven effective in curing a multi-resistant strain [47]. Thalidomide, an immunomodulator, reduced TNF-α secretion while increasing IFN-γ levels, thereby enhancing Th1 responses against a multi-resistant strain of mucosal leishmaniasis [35]. Despite the promising results of immunotherapies in humans, studies to date have been limited to small series or individual case reports.

Although immunotherapy is a relatively recent field, it shows promise but requires complex experimentation and development. Research into plant extracts has also emerged as a potential method to shift host immune responses favorably for Leishmania elimination.

Ethnopharmacology

Ethnopharmacology is a rapidly growing scientific field that integrates botany, chemistry, and pharmacology to evaluate the biological activity and scientific validity of plants traditionally used in medicine. By leveraging the knowledge of indigenous populations, this approach helps identify plants with potential for drug development. It can also save time by serving as a shortcut for discovering new active compounds.

All the compounds discussed in the in vivo studies (Table 7) were tested directly against Leishmania infections. These studies demonstrated reductions in parasite burden, often attributed to an increase in Th1 immune response and a decrease in Th2 cytokine secretion, thereby promoting host survival over parasite persistence. Several compounds have been specifically studied for their effects on Leishmania parasite clearance. Lupeol, mahanine, and extracts from Croton caudatus Geisel have been shown to upregulate reactive oxygen species (ROS) and nitric oxide (NO) pathways, both of which are critical for destroying intracellular pathogens [22, 25, 81]. Molecular docking identified specific parasite targets for some compounds. Lupeol, for example, bound to key Leishmania proteins such as PTR1, APRT, LPG, and GP63 [22]. Croton caudatus Geisel extract targets ascorbate peroxidase, a parasite antioxidant [25]. These finding suggested dual mechanisms, direct parasite targeting, and host immune modulation. In addition to their potential dual mechanisms, oral formulation of mahanine and JdHex offered easier administration compared to traditional anti-leishmanial drugs [25, 81].

Table 7

Ethnopharmacology.

Many compounds tested in vitro demonstrated direct activity against Leishmania while others targeted the cellular pathways of host cells to control the parasite (Table 7). Some compounds inhibited essential parasite enzymes, such as arginase [55, 82, 83], or trypanothione reductase [51] or both [56]. Other plants extracts exerted their effect through cytokine modulation to enhance immune responses. For instance, Tetradenia riparia essential oil increased IFN-g secretion [24]. Modulation of phagocytic activity has also been identified as a mechanism of action including enhancement of NO secretion and phagocytic activity [79, 95] or modification in the activation state of macrophages [18]. ROS production, known to be essential in intracellular parasite clearance, was also commonly observed [18, 19, 62]. While most studies highlighted compounds that act directly against Leishmania, several reported anti-leishmanial activity without detailing the underlying mechanisms [7, 11, 97, 104], making it challenging to develop these compounds as potential treatments for Leishmania.

Discussion

This review focuses on identifying specific strategies for drug development by examining recent advances in drug discovery. The WHO currently recommended monotherapies with various approved molecules as first-line treatments, depending on the region. Among these, L-AMB is one of the most effective options; however, it requires hospitalization, is costly, and is difficult to access in many countries. Recent reports of resistant strains highlight the urgent need for innovative drug development strategies to avert a crisis akin to antibiotic resistance.

To address drug resistance, combining authorized drugs has emerged as a strategy. Combinations often reduce dosage, toxicity, and costs, while increasing efficacy. However, some combinations, such as L-AMB with SSG or miltefosine [109] or combination of intralesional Glucantime® with oral itraconazole [8] showed no benefit over monotherapy. Combining miltefosine with pentamidine resulted in additive effects, but also increased side effects and costs, rendering it impractical [93]. Developing effective combinations still requires extensive trials to optimize dosing and efficacy. While lower doses can reduce cytotoxicity and costs, these challenges remain inherent to the molecules themselves and require alternative compounds to resolve fully.

Nanocarriers, such as liposomes, have successfully reduced toxicity in AMB formulations. However, the cost increased due to reliance on animal-derived cholesterol. Using plant-derived lipids like stigmasterol (DSHemsPC) has been proposed as a promising alternative. In mice, this formulation maintained AMB levels in target organs and reduced inflammation and parasite burden [43]. Nanoparticles also enable targeted delivery, delayed release, and modified administration routes [7, 11, 97, 104]. For example, nanoparticles have facilitated oral delivery of combinations such as AMB and paromomycin [73] or topical application of AMB with miltefosine [21]. They are versatile tools for improving treatments, though they significantly increase costs.

Repositioning drugs has proven valuable in neglected tropical diseases. Repositioning saves time and money, as approved drugs have existing safety data. Miltefosine is one of the successful examples. Among repositioned drugs, only fexinidazole has undergone clinical trials for leishmaniasis. Although promising in mice, it led to relapses, causing the trial to be terminated due to insufficient efficacy [74]. However, predicting the effects of immunomodulatory drugs remains challenging. For example, simvastatin reduced parasite burden in both susceptible BALB/c and resistant C57/Bl6 mice, while pravastatin improved outcomes in susceptible mice, but worsened outcomes in resistant ones [72].

Since immunity is critical for disease control, combining immunomodulating compounds with traditional treatments has been proposed. Strategies aim to stimulate pro-inflammatory responses or reduce excessive inflammation, especially in cutaneous lesions. While some approaches have reduced treatment duration and side effects, others have shown no effect [56, 58] or increased adverse reactions as seen with pentoxifylline supplementation [13]. Combining imiquimod with Glucantime® improved cure rates in L. major infections [98], but pairing it with SSG for L. braziliensis showed no statistical significance [58]. Numerous studies have tried to increase the Th1 response by favoring a pro-inflammatory environment, but there have also been trials that inhibited Th1 responses to limit local inflammation and reduce tissue damage in response to cutaneous infection [53, 85]. Although a promising strategy, immunomodulation requires further development and cannot replace chemotherapy alone.

Ethnobotany uses local knowledge to identify plants with anti-leishmanial potential. Surveys often reveal plants with broad applications, such as treating inflammation or microbial infection [22]. However, not all studies confirm traditional uses. Some extracts exhibit high cytotoxicity, rendering them unsuitable for macrophages [30, 70]. Testing on intracellular amastigotes is critical, as Girardi et al. demonstrated that compounds active against promastigotes and axenic amastigotes failed against intracellular macrophages [34]. Few studies elucidate the mechanism of action, and effects are often attributed to synergistic interactions among multiple compounds. Despite these challenges, ethnobotany remains promising. It supports biodiversity and offers cost-effective options for natural product development. Commercializing these products aligns with growing demand for safer, environmentally conscious treatments.

Conclusion

In addition to strategies such as combining treatments, using nanoparticle formulations, repositioning drugs, employing immunomodulators, and conducting ethnobotanical research, artificial intelligence (AI) has emerged as a powerful tool in drug discovery. AI can accelerate the identification and optimization of new compounds by predicting molecular properties, optimizing chemical structures, and simulating biological interactions. Finally, AI has the potential to enhance the efficiency of drug development, while significantly reducing the time and cost of research and development.

Acknowledgments

This work was supported by the Fondation pour la Recherche Médicale, grant number ECO201806006733, to A.M.

Conflicts of interest

All the authors state that there are no competing interests.

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Cite this article as: Majoor A, Michel G, Marty P, Boyer L & Pomares C. 2025. Leishmaniases: Strategies in treatment development. Parasite 32, 18. https://doi.org/10.1051/parasite/2025009.

All Tables

Table 1

Classical monotherapies used for Leishmania infection.

In the text
Table 2

Combination therapies for human leishmaniases.

In the text
Table 3

Combination therapies for canine leishmaniases.

In the text
Table 4

Nanoparticle carriers with amphotericin B.

In the text
Table 5

Nanoparticle carriers with miltefosine, pentamidine or SSG.

In the text
Table 6

Repositioned drugs and their mechanisms of action.

In the text
Table 7

Ethnopharmacology.

In the text

All Figures

thumbnail Figure 1

Current treatments and their development over time.
In the text
thumbnail Figure 2

Immunochemotherapy tested in combination with drugs against Leishmania [9, 13, 35, 47, 53, 58, 63, 66, 85, 98, 107].
In the text

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