title: The non-Geldanamycin Hsp90 inhibitors enhanced the antifungal activity of fluconazole.
abstract: The molecular chaperone heat shock protein 90 (Hsp90) is highly conserved in eukaryotes and facilitates the correct folding, productive assembly and maturation of a diverse cellular proteins. In fungi, especially the most prevalent human fungal pathogen Candida albicans, Hsp90 influences development and modulates drug resistance. Here, we mainly explore the effect of non-Geldanamycin Hsp90 inhibitor HSP990 on the activity of fluconazole (FLC) against Candida albicans and investigate the underlying mechanism. We demonstrate that HSP990 has potent synergistic antifungal activity with FLC against FLC-resistant C. albicans through the checkerboard microdilution assay,agar diffusion tests and time-kill curves, and shows low cytotoxicity to human umbilical vein endothelial cells. Further study shows that the activity of FLC against C. albicans biofilm formation in vitro is significantly enhanced when used in combination with HSP990. In a murine model of disseminated candidiasis, the therapeutic efficacy of FLC is also enhanced by the pharmacological inhibition of C. albicans Hsp90 function with HSP990. Thus, the combined use of small molecule compound and existing antifungal drugs may provide a potential therapeutic strategy for fungal infectious disease.
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine 1239 Siping Road, Shanghai 200092, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Li
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine 1239 Siping Road, Shanghai 200092, China.
authors.forename: Maomao
authors.initials: M
authors.lastname: An
authors.affiliation: Department of Laboratory Medicine, Changhai Hospital, The Second Military Medical Universiy Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine 1239 Siping Road, Shanghai 200092, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University 415 Fengyang Road, Shanghai 200433, China.
authors.forename: Xueya
authors.initials: X
authors.lastname: Yao
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine 1239 Siping Road, Shanghai 200092, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine 1239 Siping Road, Shanghai 200092, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine 1239 Siping Road, Shanghai 200092, China.
authors.forename: Shiqun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine 1239 Siping Road, Shanghai 200092, China.
authors.forename: Simin
authors.initials: S
authors.lastname: Chen
authors.affiliation: New Drug Research and Development Center, School of Pharmacy, Second Military Medical University Shanghai, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: He
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine 1239 Siping Road, Shanghai 200092, China.
authors.forename: Jundong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University 415 Fengyang Road, Shanghai 200433, China.
authors.forename: Zui
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine1239 Siping Road, Shanghai 200092, China; New Drug Research and Development Center, School of Pharmacy, Second Military Medical UniversityShanghai, China.
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Jiang
keywords: Hsp90 inhibitors; fluconazole; fungal pathogens; synergistic antifungal activity