Infection and Drug Resistance (Jun 2023)
Synergy and Mechanism of Leflunomide Plus Fluconazole Against Resistant Candida albicans: An in vitro Study
Abstract
Xiuyun Li,1,2 Ning Zhang,1 Liuping Zhang,3 Chang Liu,4 Shicun Zheng,1,* Hongxiang Lou2,* 1Maternal and Child Health Development Research Center, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, Shandong Province, 250014, People’s Republic of China; 2Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, 250012, People’s Republic of China; 3Pharmaceutical Department, Shanxian Central Hospital, Heze, Shandong Province, 274300, People’s Republic of China; 4Hospital for Reproductive Medicine Affiliated to Shandong University, Jinan, Shandong Province, 250021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shicun Zheng, Maternal and Child Health Development Research Center, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, Shandong Province, 250014, People’s Republic of China, Tel/Fax +86 531 68795001, Email [email protected] Hongxiang Lou, Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, 250012, People’s Republic of China, Tel/Fax +86 531 88382501, Email [email protected]: The global rise in the resistance of Candida albicans to conventional antifungals makes Candida albicans infections harder to treat. The main objective of this study was to investigate the antifungal effects and underlying mechanisms of leflunomide in combination with triazoles against resistant Candida albicans.Methods: In this study, the microdilution method was used to determine the antifungal effects of leflunomide in combination with three triazoles on planktonic cells in vitro. The morphological transition from yeast to hyphae was observed under a microscope. The effects on ROS, metacaspase, efflux pumps, and intracellular calcium concentration were investigated, respectively.Results: Our findings suggested that leflunomide + triazoles showed a synergistic effect against resistant Candida albicans in vitro. Further study concluded that the synergistic mechanisms were resulted from multiple factors, including the inhibited efflux of triazoles, the inhibition of yeast-to-hyphae transition, ROS increasing, metacaspase activation, and [Ca2+]i disturbance.Discussion: Leflunomide appears to be a potential enhancer of current antifungal agents for treating candidiasis caused by resistant Candida albicans. This study can also serve as an example to inspire the exploration of new approaches to treating resistant Candida albicans.Keywords: Candida albicans, triazoles, leflunomide, synergy, synergistic mechanism
