What drugs are repurposing in leishmaniasis?: An overview of new hope for a neglected disease

October 6, 2025 •

5 min read

Leishmaniasis is classified as a neglected tropical disease by the World Health Organization and is the second-leading parasitic killer globally, after malaria. The strategy of drug repurposing—the process of finding new uses for existing drugs—is providing a critical, cost-effective pathway to identify novel treatments for this parasitic infection.

Quick Summary

This article explores the landscape of drugs being repurposed for leishmaniasis, including antifungals, anticancer agents, and antibiotics. It outlines the mechanisms of action, clinical applications, and the benefits of using existing FDA-approved compounds.

Key Points

Drug Repurposing Explained: The strategy of drug repurposing involves finding new therapeutic uses for existing, approved drugs, offering a cost-effective and faster alternative to traditional drug discovery for leishmaniasis.
Miltefosine, a Repurposed Anticancer Drug: Miltefosine, originally an anticancer agent, is the only oral drug for leishmaniasis, inducing apoptosis-like cell death in the parasite, though it carries risks of resistance and teratogenicity.
Amphotericin B from Antifungal to Antileishmanial: Amphotericin B, a potent antifungal, was repurposed for leishmaniasis, with its safer liposomal formulation (AmBisome) becoming the preferred treatment for visceral leishmaniasis despite high costs.
Paromomycin, an Antibiotic for Leishmaniasis: The antibiotic paromomycin, initially for intestinal infections, effectively inhibits protein synthesis in the parasite and is used as an affordable treatment for both cutaneous and visceral leishmaniasis.
Novel Repurposed Candidates Identified: Advanced computational screening and research have identified a wide array of new repurposed candidates, including anticancer kinase inhibitors (sorafenib), antidepressants, and marine-derived compounds like onnamides.
Advantages and Challenges of Repurposing: Repurposing offers advantages like reduced development time and costs due to established safety profiles, but challenges include managing potential toxicity, overcoming drug resistance, and optimizing delivery methods.
Combination Therapies to Combat Resistance: To address emerging resistance, combination therapies—such as miltefosine with paromomycin—are increasingly being utilized to enhance efficacy, shorten treatment duration, and improve patient outcomes.

The Urgent Need for Repurposed Drugs

Leishmaniasis affects millions in endemic areas, yet the development of new treatments remains challenging and costly due to low financial incentives. The standard treatments, including pentavalent antimonials, have been in use for decades and face significant limitations, such as high toxicity, expensive and prolonged administration, and widespread drug resistance. In response, drug repurposing has emerged as a promising alternative, leveraging existing drugs with known safety profiles to accelerate the discovery and deployment of new therapies. This strategy significantly reduces the time and cost associated with the traditional drug development process.

Prominent Classes of Repurposed Medications

Several classes of drugs have been repurposed for their anti-leishmanial activity, exploiting similarities in the biology of the parasites and other pathogens or cancer cells.

Antifungal Agents

Antifungals, particularly those targeting the ergosterol biosynthesis pathway, have shown significant efficacy because Leishmania parasites also use ergosterol as a key component of their cell membranes, unlike human cells which use cholesterol.

Amphotericin B (AmB): A polyene antifungal, AmB is a cornerstone of leishmaniasis therapy. Its mechanism involves binding to ergosterol in the parasite's cell membrane, creating pores that cause the cell to leak and die. While the original deoxycholate form was highly toxic, a repurposed liposomal formulation (AmBisome) has a better safety profile and is the drug of choice for visceral leishmaniasis (VL) in many regions.
Azole Drugs: This class includes drugs like itraconazole and fluconazole, which inhibit the parasite's lanosterol 14-alpha demethylase enzyme, disrupting ergosterol synthesis. While their efficacy can be strain-dependent, they offer a less toxic oral treatment option for cutaneous leishmaniasis (CL).

Anticancer Drugs

Given their potent antiproliferative properties, several anticancer agents have been investigated for repurposing against Leishmania, which relies on rapid cell division to spread.

Miltefosine: Originally developed as an antineoplastic agent, miltefosine is the first and only oral drug approved for treating leishmaniasis. It induces an apoptosis-like cell death in the parasite by interfering with lipid metabolism and cell signaling. The oral route of administration offers significant advantages for patient adherence, though resistance and teratogenicity are concerns.
Kinase Inhibitors: Recent research has identified protein kinase inhibitors, such as sorafenib and imatinib, as potential candidates. These drugs target specific protein kinases essential for parasite survival, demonstrating potent anti-proliferative effects in experimental models of VL.

Antibiotics

Certain antibiotics initially developed for other pathogens have proven effective against Leishmania.

Paromomycin: This aminoglycoside antibiotic was originally used for intestinal protozoan infections. It inhibits protein synthesis by binding to the parasite's ribosomal RNA and is effective against both CL and VL. It is used as both a topical and injectable therapy.
Ivermectin: The broad-spectrum antiparasitic ivermectin has shown effectiveness against Leishmania in experimental studies, particularly when delivered via novel formulations like polymeric micelles.

Other Repurposed Compounds

Innovative research has identified additional compounds from diverse therapeutic areas with anti-leishmanial potential.

Nitroimidazoles: Drugs like fexinidazole and delamanid, initially developed for other parasitic infections or tuberculosis, have shown potent activity against Leishmania by inhibiting DNA synthesis.
Local Anesthetics: A surprising class of candidates includes local anesthetics like dibucaine and prilocaine, which have shown inhibitory effects on the parasite in vitro. Dibucaine, for example, proved comparable to standard treatments in hamsters.
Marine-Derived Compounds: Newly identified compounds like onnamides from marine sponges demonstrate high potency and a distinct mechanism of action, offering a pathway to overcome existing drug resistance.

Comparison of Repurposed Drugs for Leishmaniasis


Drug (Original Class)	Mechanism of Action	Advantages	Disadvantages	Stage of Use	Target Indication(s)
Miltefosine (Anticancer)	Disrupts lipid metabolism; induces apoptosis-like death.	Oral administration, high bioavailability.	Teratogenicity, potential for resistance, gastrointestinal side effects.	Approved and in clinical use.	VL, CL, MCL.
Amphotericin B (Liposomal) (Antifungal)	Binds to ergosterol in parasite membrane, causing membrane disruption.	Less toxic formulation, effective against resistant strains.	High cost, requires intravenous administration.	Approved and in clinical use.	VL (first-line), resistant cases.
Paromomycin (Antibiotic)	Inhibits protein synthesis by targeting ribosomal RNA.	Affordable, good efficacy, used topically or intramuscularly.	Can cause nephrotoxicity and ototoxicity, injection site pain.	Approved and in clinical use.	VL, CL.
Itraconazole (Antifungal)	Inhibits ergosterol biosynthesis via CYP450-dependent enzyme.	Oral formulation, potentially lower toxicity than systemic options.	Variable efficacy, resistance, hepatotoxicity risk.	Clinical use (second-line).	CL.
Sorafenib/Imatinib (Anticancer)	Inhibits parasite protein kinases crucial for survival.	Novel targets for combating resistance.	Early stage of development, potential for off-target effects.	Experimental/Preclinical.	VL.

The Promise and Challenges of Repurposing

The success stories of repurposed drugs like amphotericin B and miltefosine demonstrate the potential of this strategy. These drugs offer several benefits:

Reduced Development Costs and Time: Since safety and manufacturing data for these drugs already exist, the process of bringing them to market for a new indication is faster and cheaper.
Established Safety Profiles: Repurposing avoids the high rate of attrition seen in de novo drug discovery, where many candidates fail due to unforeseen toxicity.
New Mechanisms of Action: Repurposed drugs often target pathways distinct from traditional anti-leishmanials, helping to circumvent drug resistance.

However, challenges remain. A significant hurdle is the potential for adverse side effects, even with a known safety profile. For example, miltefosine's teratogenicity restricts its use in pregnant women. The emergence of resistance is also a concern for repurposed drugs, necessitating combination therapies to improve outcomes and mitigate resistance development. Furthermore, the specific mechanism of action in Leishmania often needs further elucidation, as seen with local anesthetics and domperidone.

The Future of Anti-Leishmanial Drug Repurposing

The future of drug repurposing for leishmaniasis is bright, fueled by advanced technologies and international collaborations. Computational methods, including machine learning and virtual screening, are now being used to rapidly identify and prioritize promising candidates from existing drug libraries. This has already led to the identification of potential candidates like valrubicin, ciclesonide, and domperidone. Continued research into novel drug delivery systems, such as nanoparticles and liposomes, also holds promise for reducing toxicity and improving the efficacy of existing drugs. By accelerating the discovery of new therapies and mitigating development risks, drug repurposing will continue to play a vital role in addressing this neglected tropical disease. The collaborative efforts of initiatives like the Drugs for Neglected Diseases Initiative (DNDi) are crucial in bringing these repurposed therapies through clinical development and to the patients who need them most.

Conclusion

Drug repurposing represents a powerful and practical strategy for advancing treatment options for leishmaniasis. By capitalizing on existing pharmacological knowledge, researchers have successfully identified numerous repurposed drugs, from antifungals and anticancer agents to antibiotics and anesthetics, that offer effective and sometimes more accessible alternatives to traditional therapies. While challenges like toxicity and resistance persist, the ongoing application of advanced computational methods and innovative delivery systems promises to further unlock the potential of repurposed drugs, bringing renewed hope for millions affected by this devastating parasitic disease.

Frequently Asked Questions

Drug repurposing for leishmaniasis involves using existing drugs, originally approved for other medical conditions, to treat this parasitic infection. This approach is more time and cost-efficient than developing new drugs from scratch.

Miltefosine is the only oral drug that was successfully repurposed for leishmaniasis. Initially an anticancer drug, it is now used to treat all forms of leishmaniasis, though its use is restricted in pregnant women due to teratogenicity.

Amphotericin B, a polyene antifungal, is repurposed because it binds to ergosterol in the parasite's membrane, which is similar to the mechanism used against fungi. A safer, liposomal formulation has become the standard of care for visceral leishmaniasis.

Yes, antibiotics like paromomycin have been repurposed. Paromomycin works by interfering with the parasite's protein synthesis and has shown effectiveness in treating both visceral and cutaneous leishmaniasis.

Beyond common examples, researchers are exploring drugs like anticancer kinase inhibitors (sorafenib), antidepressants (sertraline), and local anesthetics (dibucaine). Computational screening methods are crucial for identifying these candidates.

Drug repurposing is vital for neglected tropical diseases because it bypasses the massive investment and long timelines of new drug development, which are often not financially viable for diseases affecting impoverished populations.

Limitations include potential toxicity issues, as seen with older formulations of amphotericin B, the emergence of drug resistance, and the high cost of some advanced formulations, which can hinder access in endemic areas.