Ketoconazole/calix[n]arenes-based compounds improve the antifungal activity against azole-resistant Candida isolates

Ketoconazole (KTZ) is an antifungal agent; however, its bioavailability and therapeutic efficacy are reduced by the low aqueous solubility of the drug. Aiming at providing to improve the biopharmaceutical properties of KTZ, we studied the water-soluble different calix[n]arenes as carrier systems for KTZ. All calix[n]areneKTZ tested showed in vitro antifungal activity superior or similar to free KTZ against Candida spp. The CX6Na/ KTZ obtained by physical mixture and freeze-drying methods were the most active, decreasing KTZ concentrations required for growth inhibition against azole-resistant isolates (e.g., C. auris). Moreover, CX6Na/KTZ showed no toxic effect on Galleria mellonella larvae and the treatment of infected larvae with C. albicans and C. auris was effective at a lower dose compared with free KTZ. Thus, CX6Na/KTZ may have a potential approach to treat mycosis, especially by improvement of KTZ inhibitory activity against azole-resistant Candida.

Automated summary

Water-soluble calix[n]arenes can be used as carrier systems for KTZ to improve its biopharmaceutical properties. CX6Na/KTZ showed superior inhibitory activity against azole-resistant Candida compared to free KTZ, and had no toxic effects on Galleria mellonella larvae.