Repurposing topical triclosan for cutaneous leishmaniasis: Preclinical efficacy in a murine Leishmania (L.) amazonensis model

Abstract

Leishmaniasis remains an important neglected tropical infection caused by the protozoan Leishmania and affects 12 million people in 98 countries. The treatment is limited with severe adverse effects. In the search for new therapies, the drug repositioning and combination therapy have been successfully applied to neglected diseases. The aim of the present study was to evaluate the in vitro and in vivo anti‐Leishmania (Leishmania) amazonensis potential of triclosan, an approved topical antimicrobial agent used for surgical procedures. in vitro phenotypic studies of drug‐treated parasites were performed to evaluate the lethal action of triclosan, accompanied by an isobolographic ex‐vivo analysis with the association of triclosan and miltefosine. The results showed that triclosan has activity against L. (L.) amazonensis intracellular amastigotes, with a 50% inhibitory concentration of 16 μM. By using fluorescent probes and transmission electron microscopy, a pore‐forming activity of triclosan toward the parasite plasma membrane was demonstrated, leading to depolarization of the mitochondrial membrane potential and reduction of the reactive oxygen species levels in the extracellular promastigotes. The in vitro interaction between triclosan and miltefosine in the combination therapy assay was classified as additive against intracellular amastigotes. Leishmania‐infected mice were treated with topical triclosan (1% base cream for 14 consecutive days), and showed 89% reduction in the parasite burden. The obtained results contribute to the investigation of new alternatives for the treatment of cutaneous leishmaniasis and suggest that the coadministration of triclosan and miltefosine should be investigated in animal models.

Triclosan: A Small Molecule with Controversial Roles

“…Recently, topical TCS and some derivatives have been also proposed for the treatment of cutaneous leishmaniasis, an important neglected tropical infection that is caused by the protozoan Leishmania and affecting 12 million people in 98 countries. TCS has shown preclinical efficacy in a murine Leishmania amazonensis model, suggesting that the parasite plasma membrane may be a possible target of the drug, leading to an irreversible lethal antiparasitic effect [ 260 ]. Otero et al (2017) [ 261 ] reported some triclosan-caffeic acid hybrids with antiprotozoal activity, which act by blocking the iron utilization by the parasite and the loss of mitochondrial transmembrane potential.…”

Recent research brings hope for reshaping the co‐evolutionary arms race against parasitic infectious diseases

“…They associated this tool to a simple and robust 96 well‐plate phenotypic assay, which was successfully employed for the screening of a small library of compounds (alkaloids, rare sugars, peptides, polyheterocycles, quinones, selenosugars, aromatic linker derivatives, and singletons), which could be used in future for the screening of new compound libraries in an affordable manner. In a second work, Mesquita et al (Mesquita et al, 2021) explored the potential of drug repurposing for leishmaniases treatment with triclosan, an approved topical antimicrobial agent used for surgical procedures. In vitro combination of triclosan and miltefosine resulted in additive effect against Leishmania amazonensis intracellular amastigotes and this co‐administration is yet to be validated in animal models as a hope for new alternative treatments.…”