title: Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.
abstract: Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2). The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane).
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China.|Department of Pharmacy, Ordos Central Hospital, Ordos, 017000, Inner Mongolia, People's Republic of China.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Translational Medicine Research Centre, Qianfoshan Hospital Affiliated to Shandong University, Jinan, 250014, Shandong Province, People's Republic of China.
authors.forename: Longtao
authors.initials: L
authors.lastname: Yue
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China.
authors.forename: Wenrui
authors.initials: W
authors.lastname: Gu
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong Province, People's Republic of China.
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Taishan Medical University, taian, 271000, Shandong Province, People's Republic of China.
authors.forename: Liuping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Qianfoshan Hospital Affiliated to Shandong University, Jinan, 250014, Shandong Province, People's Republic of China.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Sun
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D002121:Calcium Channel Blockers; D005656:Fungal Proteins; D015725:Fluconazole