Approved drugs successfully repurposed against Leishmania based on machine learning predictions

Area of Science:

• Parasitology
• Drug Discovery
• Computational Biology

Background:

• Drug repurposing offers a cost-effective strategy for discovering novel treatments for Neglected Tropical Diseases like Leishmaniases.
• Previous work established a Machine Learning pipeline to identify FDA-approved drugs with potential antileishmanial activity.
• This study focuses on the in vitro validation of ten drug candidates predicted by this computational approach.

Purpose of the Study:

• To validate the in vitro antileishmanial efficacy of ten FDA-approved drugs identified through Machine Learning.
• To assess the activity of these drug candidates against promastigote and amastigote forms of Leishmania infantum and Leishmania major.
• To identify novel antileishmanial agents and confirm previously predicted compounds.

Main Methods:

• An MTT assay was employed to evaluate the activity of ten drug candidates against promastigotes of L. infantum and L. major.
• Standard antileishmanial drug Amphotericin B served as the positive control.
• Cytotoxicity was assessed against THP-1-derived macrophages, and activity against intracellular amastigotes was determined.

Main Results:

• Five out of ten tested drugs exhibited significant antileishmanial effects.
• Dibucaine and Domperidone showed potent activity (IC50 ≤ 8.17 µg/mL) against promastigotes and amastigotes.
• Acebutolol, Prilocaine, and Phenylephrine demonstrated antileishmanial activity, with Acebutolol and Prilocaine showing notable efficacy.
• All tested compounds were non-toxic to macrophages at effective concentrations.

Conclusions:

• The study successfully validated the Machine Learning approach for drug repurposing against Leishmania parasites.
• Dibucaine and Domperidone confirmed their antileishmanial potential, supporting previous in vivo findings.
• Acebutolol, Prilocaine, and Phenylephrine emerged as novel antileishmanial drug candidates warranting further investigation.