Repurposing non-antifungal drugs auranofin and pentamidine in combination as fungistatic antifungal agents against C. albicans
Jiaying Lin, Xueyi Xiao, Yijing Liang, Huimin Zhao, Yingxiao Yu, Peiyan Yuan, Sha Lu, Xin Ding
Abstract
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.