In vitro antileishmanial activity of ravuconazole, a triazole antifungal drug, as a potential treatment for leishmaniasis
| Autor: | Wanderley de Souza, Joseane Lima Prado Godinho, Juliany Cola Fernandes Rodrigues, Sara Teixeira de Macedo Silva, Gonzalo Visbal, Julio A. Urbina |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Leishmania mexicana 030106 microbiology Antiprotozoal Agents Triazole Antifungal drug Mitochondrion Pharmacology Ravuconazole Mass Spectrometry Inhibitory Concentration 50 03 medical and health sciences chemistry.chemical_compound Parasitic Sensitivity Tests medicine Fluorometry Pharmacology (medical) Viability assay Amastigote biology Drug Repositioning Leishmaniasis Triazoles Flow Cytometry Leishmania biology.organism_classification medicine.disease Microscopy Electron Thiazoles Infectious Diseases Microscopy Fluorescence chemistry |
| Zdroj: | Journal of Antimicrobial Chemotherapy. 73:2360-2373 |
| ISSN: | 1460-2091 0305-7453 |
| Popis: | Objectives Leishmaniasis, one of the most significant neglected diseases around the world, is caused by protozoan parasites of the Leishmania genus. Nowadays, the available aetiological treatments for leishmaniasis have variable effectiveness and several problems such as serious side effects, toxicity, high cost and an increasing number of resistance cases. Thus, there is an urgent need for safe, oral and cost-effective drugs for leishmaniases. Previously, our group has shown the effect of the ergosterol biosynthesis inhibitors on Leishmania amazonensis. Herein, we showed the effect of ravuconazole against L. amazonensis; ravuconazole is a second-generation triazole antifungal drug that has good bioavailability after oral administration and a long terminal half-life in humans, a broad activity spectrum, high effectiveness in treatment of mycosis and negligible side effects. Methods Several methodologies were used: cell culture, fluorescence and electron microscopy, high-resolution capillary GC coupled with MS, fluorimetry and flow cytometry. Results Our results showed that ravuconazole was able to inhibit the proliferation of L. amazonensis promastigotes and intracellular amastigotes in vitro, with single-digit to sub-micromolar IC50 values, causing several alterations in the morphology, ultrastructure, cell viability and physiology of the parasites. The mitochondrion was significantly affected by the treatment, resulting in a collapse of the mitochondrial transmembrane potential that consequently led to inhibition of ATP production, combined with an increase in reactive oxygen species and mitochondrial superoxide production; by transmission electron microscopy, the organelle displayed a completely altered ultrastructure. The treatment changed the lipid profile, showing a profound depletion of the 14-desmethyl endogenous sterol pool. Conclusions These results suggest that ravuconazole could be an alternative option for the treatment of leishmaniasis. |
| Databáze: | OpenAIRE |
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