Oral clioquinol is effective in the treatment of a fly model of Candida systemic infection

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Background Clioquinol was used in the 1950s‐1970s as antimicrobial but its oral formulations were withdrawn from the market due to suspected neurotoxicity.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.

Antifungal activity and toxicological parameters of 8‐hydroxyquinoline‐5‐sulfonamides using alternative animal models

“…Clioquinol (5‐chloro‐7‐iodo‐8‐hydroxyquinoline) has also fully protected C. albicans ‐infected flies (Pippi et al . 2019a). Such as clioquinol, PH151 and PH153 have inhibited pseudohyphae formation in C. albicans (Pippi et al .…”

“…To determine whether the 8‐hydroxyquinoline‐5‐sulfonamides treatment protects flies against candidiasis, groups of 15 Tl‐deficient female flies were housed in empty vials for 6–8 h to starve them and then transferred to vials with food containing 100 µ L of PH151 and PH153 at the concentration of 1 mg ml −1 , as previously described (Pippi et al . 2019a). After 24 h, a needle that had been dipped into a 0·85% NaCl solution containing 10 8 C. albicans yeast cells per ml was injected in the dorsal side thorax of the CO 2 ‐anesthetized flies.…”

“…2008; Pippi et al . 2019a). Positive control was provided by infecting flies that were not exposed to compounds, whereas for negative control flies were punctured with a needle that was dipped into sterile saline.…”

“…The number of colony forming units (CFU) was counted after 48 h of incubation at 35°C (Pippi et al . 2019a). The same procedure was performed with the untreated control group.…”

“…Fly strains were a gift from Dr. Dimitrios Kontoyiannis from the University of Texas MD Anderson Cancer Center. Standard procedures were used for manipulation, feeding and housing of flies in all experiments (Chamilos et al 2008;Pippi et al 2019a).…”