title: Synergistic Effects of Tetrandrine with Posaconazole Against Aspergillus fumigatus.
abstract: In our earlier in vitro and in vivo studies, synergistic effects were observed when itraconazole or voriconazole were combined with tetrandrine (TET) against Aspergillus fumigatus, and the synergistic mechanism was related to inhibition of the drug efflux pump. Posaconazole (PCZ) is a broad-spectrum triazole antifungal agent used for the treatment of diverse fungal infections, including aspergillosis and candidiasis. Herein, the antifungal effects of TET are further investigated in vitro and in vivo alone or combined with PCZ against 20 clinical isolates of A. fumigatus. We found that the minimal inhibitory concentrations (MICs) of PCZ were decreased one- to twofold and three- to fivefold across a series of concentration gradients in vitro in presence of TET. Time-killing curves revealed that the synergy was dependent on TET and PCZ concentrations as well as incubation time. The combination could further downregulate the expression of MDR2, MDR3, MDR4, and ATRF in PCZ-resistant strain, however, it has subtle effects on TET-synergized mechanism. In addition, TET in combination with PCZ significantly prolonged mice survival time and reduced kidney and brain tissue burdens in vivo. Our data in vitro and in vivo demonstrate that TET is an effective synergist with azoles against A. fumigates.
authors.affiliation: 1 The First Affiliated Hospital, Jinan University , Guangzhou, People's Republic of China .|2 Institute of Mycology, Jinan University , Guangzhou, People's Republic of China .
authors.forename: Shui-Xiu
authors.initials: SX
authors.lastname: Li
authors.affiliation: 1 The First Affiliated Hospital, Jinan University , Guangzhou, People's Republic of China .|2 Institute of Mycology, Jinan University , Guangzhou, People's Republic of China .
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Song
authors.affiliation: 1 The First Affiliated Hospital, Jinan University , Guangzhou, People's Republic of China .|2 Institute of Mycology, Jinan University , Guangzhou, People's Republic of China .
authors.forename: Ling
authors.initials: L
authors.lastname: Jiang
authors.affiliation: 1 The First Affiliated Hospital, Jinan University , Guangzhou, People's Republic of China .|2 Institute of Mycology, Jinan University , Guangzhou, People's Republic of China .
authors.forename: Ya-Jing
authors.initials: YJ
authors.lastname: Zhao
authors.affiliation: 1 The First Affiliated Hospital, Jinan University , Guangzhou, People's Republic of China .|2 Institute of Mycology, Jinan University , Guangzhou, People's Republic of China .
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: 3 Department of Microbiology and Immunology, Georgetown University Medical Center , Washington, District of Columbia.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Li
authors.affiliation: 1 The First Affiliated Hospital, Jinan University , Guangzhou, People's Republic of China .|2 Institute of Mycology, Jinan University , Guangzhou, People's Republic of China .
authors.forename: Kun-Ju
authors.initials: KJ
authors.lastname: Zhu
authors.affiliation: 1 The First Affiliated Hospital, Jinan University , Guangzhou, People's Republic of China .|2 Institute of Mycology, Jinan University , Guangzhou, People's Republic of China .
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy; D001232:Aspergillus fumigatus / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002177:Candidiasis / Q000188:drug therapy; D025141:Drug Resistance, Fungal / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests / Q000379:methods; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D044182:Benzylisoquinolines; D014230:Triazoles; C009438:tetrandrine; D017964:Itraconazole; C101425:posaconazole; D065819:Voriconazole
keywords: Aspergillus fumigatus; antifungal resistance; posaconazole (PCZ); synergistic effect; tetrandrine (TET)