Bruna Pippi1, Simone Merkel2, Keli Jaqueline Staudt3, Mario Lettieri Teixeira4, Bibiana Verlindo de Araújo3, Régis Adriel Zanette2, Saulo Fernandes Andrade1,3, Alexandre Meneghello Fuentefria1,3. 1. Programa de Pós-Graduação em Microbiologia Agrícola e do Ambiente, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 2. Programa de Pós-Graduação em Ciências Biológicas: Farmacologia e Terapêutica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 3. Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 4. Laboratório de Farmacologia, Instituto Federal Catarinense, Concórdia, Brazil.
Abstract
BACKGROUND: Clioquinol was used in the 1950s-1970s as antimicrobial but its oral formulations were withdrawn from the market due to suspected neurotoxicity. Currently, there is possibility of repositioning of oral clioquinol formulations. OBJECTIVES: To evaluate the antifungal activity and toxicological parameters of clioquinol and the other two 8-hydroxyquinoline derivatives using alternative animal models and to study the interaction dynamic of clioquinol with Candida albicans. METHODS: We used Toll-deficient Drosophila melanogaster to test the protective effect of 8-hydroxyquinolines against C. albicans infection. Toxicological parameters were investigated in chicken embryo. A mathematical model-based analysis of the time-kill data of clioquinol was performed to obtain pharmacodynamic characteristics. RESULTS: Clioquinol fully protected D. melanogaster from the infection. The 8-hydroxyquinolines did not cause changes in opening of the beak and movement of the chicken embryo; however, clioquinol and compound 2 increased arterial pulsation. Compound 3 was lethal at 1 mg mL-1 . Effective concentration found in modelling indicated that clioquinol was highly effective against C. albicans (0.306 μg mL-1 ) in easily achievable serum levels; clioquinol rapidly achieved kill rate reaching the maximum effect after 13 hours. CONCLUSIONS: These results support the potential of clioquinol to be used as a systemic antifungal agent.
BACKGROUND:Clioquinol was used in the 1950s-1970s as antimicrobial but its oral formulations were withdrawn from the market due to suspected neurotoxicity. Currently, there is possibility of repositioning of oral clioquinol formulations. OBJECTIVES: To evaluate the antifungal activity and toxicological parameters of clioquinol and the other two 8-hydroxyquinoline derivatives using alternative animal models and to study the interaction dynamic of clioquinol with Candida albicans. METHODS: We used Toll-deficient Drosophila melanogaster to test the protective effect of 8-hydroxyquinolines against C. albicans infection. Toxicological parameters were investigated in chicken embryo. A mathematical model-based analysis of the time-kill data of clioquinol was performed to obtain pharmacodynamic characteristics. RESULTS:Clioquinol fully protected D. melanogaster from the infection. The 8-hydroxyquinolines did not cause changes in opening of the beak and movement of the chicken embryo; however, clioquinol and compound 2 increased arterial pulsation. Compound 3 was lethal at 1 mg mL-1 . Effective concentration found in modelling indicated that clioquinol was highly effective against C. albicans (0.306 μg mL-1 ) in easily achievable serum levels; clioquinol rapidly achieved kill rate reaching the maximum effect after 13 hours. CONCLUSIONS: These results support the potential of clioquinol to be used as a systemic antifungal agent.
Authors: Yu-Shan Cheng; Jose Santinni Roma; Min Shen; Caroline Mota Fernandes; Patricia S Tsang; He Eun Forbes; Helena Boshoff; Cristina Lazzarini; Maurizio Del Poeta; Wei Zheng; Peter R Williamson Journal: Antimicrob Agents Chemother Date: 2021-03-18 Impact factor: 5.191