title: The Synergistic Effect of Azoles and Fluoxetine against Resistant Candida albicans Strains Is Attributed to Attenuating Fungal Virulence.
abstract: This study evaluated the synergistic effects of the selective serotonin reuptake inhibitor, fluoxetine, in combination with azoles against Candida albicans both in vitro and in vivo and explored the underlying mechanism. MICs, sessile MICs, and time-kill curves were determined for resistant C. albicans Galleria mellonella was used as a nonvertebrate model for determining the efficacy of the drug combinations against C. albicans in vivo For the mechanism study, gene expression levels of the SAP gene family were determined by reverse transcription (RT)-PCR, and extracellular phospholipase activities were detected in vitro by the egg yolk agar method. The combinations resulted in synergistic activity against C. albicans strains, but the same effect was not found for the non-albicans Candida strains. For the biofilms formed over 4, 8, and 12 h, synergism was seen for the combination of fluconazole and fluoxetine. In addition, the time-kill curves confirmed the synergism dynamically. The results of the G. mellonella studies agreed with the in vitro analysis. In the mechanism study, we observed that fluconazole plus fluoxetine caused downregulation of the gene expression levels of SAP1 to SAP4 and weakened the extracellular phospholipase activities of resistant C. albicans The combinations of azoles and fluoxetine showed synergistic effects against resistant C. albicans may diminish the virulence properties of C. albicans.
authors: School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong Province, People's Republic of China.
authors: Wenrui
authors: W
authors: Gu
authors: Department of Out-Patient, Qianfoshan Hospital Affiliated to Shandong University, Jinan, People's Republic of China.
authors: Dongmei
authors: D
authors: Guo
authors: School of Pharmaceutical Sciences, Taishan Medical University, Taian, Shandong Province, People's Republic of China.
authors: Liuping
authors: L
authors: Zhang
authors: Department of Nephrology, Qianfoshan Hospital Affiliated to Shandong University, Jinan, People's Republic of China.
authors: Dongmei
authors: D
authors: Xu
authors: Department of Pharmacy, Qianfoshan Hospital Affiliated to Shandong University, Jinan, Shandong Province, People's Republic of China sunshujuan888@163.com.
authors: Shujuan
authors: S
authors: Sun
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001393:Azoles / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D004353:Drug Evaluation, Preclinical / Q000379:methods; D025141:Drug Resistance, Fungal / Q000187:drug effects; D004357:Drug Synergism; D005473:Fluoxetine / Q000494:pharmacology*; D005656:Fungal Proteins / Q000378:metabolism; D007814:Larva / Q000187:drug effects / Q000382:microbiology; D008826:Microbial Sensitivity Tests / Q000379:methods; D009036:Moths / Q000382:microbiology; D010740:Phospholipases / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014774:Virulence / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D016282:Aspartic Acid Endopeptidases; D001393:Azoles; D005473:Fluoxetine; D005656:Fungal Proteins; D010740:Phospholipases; D017367:Selective Serotonin Reuptake Inhibitors; C086390:SAP1 protein, Candida albicans; C086392:SAP4 protein, Candida albicans