New insights into the mechanism of antifungal action of 8-hydroxyquinolines

Abstract

The 8-hydroxyquinoline core is a privileged scaffold for drug design explored to afford novel derivatives endowed with biological activity. Our research aimed at clarifying the antifungal mechanism of action of clioquinol, 8-hydroxy-5-quinolinesulfonic acid, and 8-hydroxy-7-iodo-5-quinolinesulfonic acid (three 8-hydroxyquinoline derivatives). The antifungal mode of action of these derivatives on Candida spp. and dermatophytes was investigated using sorbitol protection assay, cellular leakage effect, ergosterol binding assay, and scanning electron microscopy. Clioquinol damaged the cell wall and inhibited the formation of pseudohyphae by C. albicans. The 8-hydroxy-5-quinolinesulfonic acid derivatives compromised the functional integrity of cytoplasmic membranes. To date no similar report was found about the antifungal mechanism of 8-hydroxyquinolines. These results, combined with the broad antifungal spectrum already demonstrated previously, reinforce the potential of 8-hydroxyquinolines for the development of new drugs.

8‐Hydroxyquinoline‐5‐sulfonamides are promising antifungal candidates for the topical treatment of dermatomycosis

“…However, MICs remain unchanged to PH151 and PH153 in the presence of external ergosterol indicating that they do not act by binding to membrane ergosterol. The other 8‐hydroxyquinoline derivatives studied by our group showed similar results (Pippi et al ).…”

“…These findings demonstrate a strong effect of these compounds on C. albicans morphogenesis, which can be considered a potential mode of action for this molecule. Clioquinol also presents these characteristics, however, the derivatives containing sulphonic acid previously studied did not show the pseudohyphae inhibitory effect (Pippi et al ). Furthermore, the presence of the large round cells when C. albicans was treated with PH151 was also observed in the SEM of cells exposed to 8‐hydroxy‐7‐iodo‐5‐quinolinesulfonic acid (Pippi et al ).…”

“…Previous studies conducted by our group have demonstrated the effect on the fungal wall of other 8‐hydroxyquinoline derivatives, such as clioquinol and derivatives containing sulphonic acid (8‐hydroxy‐5‐quinolinesulfonic acid and 8‐hydroxy‐7‐iodo‐5‐quinolinesulfonic acid). However, the effect of sulphonic acids was species dependent (Pippi et al ). Furthermore, 8‐hydroxy‐5‐quinolinesulfonic acid derivatives also showed action on the fungal cell membrane, such as the alteration of the cell permeability of Candida spp.…”

“…Furthermore, 8‐hydroxy‐5‐quinolinesulfonic acid derivatives also showed action on the fungal cell membrane, such as the alteration of the cell permeability of Candida spp. and dermatophytes were detected through leakage of cellular material assay (Pippi et al ). In contrast, data obtained by measuring the UV‐absorbing materials revealed that PH151 and PH153 did not show such an effect.…”

“…The leakage of cellular material was assessed by measuring 260 nm absorbing materials released into the medium, especially the uracil nucleotide, which exhibits the strongest absorbance (Lunde and Kubo, ). The assay was carried out with one representative strain of each genus studied ( C. albicans ATCC 18804, M. canis MCA 01 and T. mentagrophytes TME 40) and the procedures were conducted as previously described (Pippi et al ). Candida cells cultured at 35 °C for 48 h on SDA (Sabouraud Dextrose Agar; HiMedia, Mumbai, India) were washed three times (3000 g for 10 min, Spinlab SL‐5M; Ribeirão Preto, SP, Brazil) and diluted to approximately 1–5 × 10 6 cells per ml with cold 0·16 mol l −1 MOPS buffer, pH 7.…”