Repurposing non-antifungal drugs auranofin and pentamidine in combination as fungistatic antifungal agents against C. albicans

• DOI: 10.3389/fcimb.2022.1065962
• Publication Date: 2022-12-15T11:26:52Z
• Authors: Jiaying Lin; Xueyi Xiao; Yijing Liang; Huimin Zhao; Yingxiao Yu; Peiyan Yuan; Sha Lu; Xin Ding
• Keywords: 0301 basic medicine; Antifungal Agents; drug repurposing; auranofin; Drug Repositioning; Microbial Sensitivity Tests; Microbiology; QR1-502; 3. Good health; 03 medical and health sciences; Cellular and Infection Microbiology; pentamidine; Auranofin; Candida albicans; combination treatment; antifungals; Pentamidine

Fungal infection is a serious global health issue, causing approximately 1.5 million mortalities annually. However, clinically available anti-fungal drugs are limited, especially for multidrug-resistant fungal infections. Therefore, new antifungal drugs are urgently needed to address this clinical challenge. In this study, we proposed two non-antifungal drugs, auranofin and pentamidine, in combination to fight against multidrug-resistant C. albicans. The insufficient antifungal activity of anti-rheumatic drug auranofin is partially due to fungal membrane barrier preventing the drug uptake, and anti-protozoal drug pentamidine was used here to improve the permeability of membrane. The auranofin/pentamidine combination displayed synergistic inhibitory effect against both drug-susceptible and drug-resistant C. albicans, as well as biofilm, and significantly reduced the minimum inhibitory concentration of each drug. At non-antifungal concentration, pentamidine can disrupt the membrane integrity and increase membrane permeability, leading to enhanced cellular uptake of auranofin in C. albicans. This repurposing strategy using the combination of non-antifungal drugs with complementary antifungal mechanism may provide a novel approach for discovery of antifungal drugs to fight against multidrug-resistant fungal infections.