title: High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections.
abstract: The high mortality rate of immunocompromised patients with fungal infections and the limited availability of highly efficacious and safe agents demand the development of new antifungal therapeutics. To rapidly discover such agents, we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products. Specifically, a microbial natural product library was screened for hits that synergize the effect of a low dosage of ketoconazole (KTC) that alone shows little detectable fungicidal activity. Through screening of approximately 20,000 microbial extracts, 12 hits were identified with broad-spectrum antifungal activity. Seven of them showed little cytotoxicity against human hepatoma cells. Fractionation of the active extracts revealed beauvericin (BEA) as the most potent component, because it dramatically synergized KTC activity against diverse fungal pathogens by a checkerboard assay. Significantly, in our immunocompromised mouse model, combinations of BEA (0.5 mg/kg) and KTC (0.5 mg/kg) prolonged survival of the host infected with Candida parapsilosis and reduced fungal colony counts in animal organs including kidneys, lungs, and brains. Such an effect was not achieved even with the high dose of 50 mg/kg KTC. These data support synergism between BEA and KTC and thereby a prospective strategy for antifungal therapy.
authors.affiliation: Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, China. zhanglixin@im.ac.cn
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhang
authors.forename: Kezhi
authors.initials: K
authors.lastname: Yan
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ren
authors.initials: R
authors.lastname: Huang
authors.forename: Jiang
authors.initials: J
authors.lastname: Bian
authors.forename: Chuansen
authors.initials: C
authors.lastname: Zheng
authors.forename: Haixiang
authors.initials: H
authors.lastname: Sun
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Chen
authors.forename: Nuo
authors.initials: N
authors.lastname: Sun
authors.forename: Rong
authors.initials: R
authors.lastname: An
authors.forename: Fangui
authors.initials: F
authors.lastname: Min
authors.forename: Weibo
authors.initials: W
authors.lastname: Zhao
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhuo
authors.forename: Jianlan
authors.initials: J
authors.lastname: You
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Song
authors.forename: Zhenyan
authors.initials: Z
authors.lastname: Yu
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Keqian
authors.initials: K
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.forename: Huanqin
authors.initials: H
authors.lastname: Dai
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Chengzhang
authors.initials: C
authors.lastname: Fu
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
authors.forename: Jintao
authors.initials: J
authors.lastname: Liu
authors.forename: Si
authors.initials: S
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Goodfellow
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jun
authors.initials: J
authors.lastname: Kuai
authors.forename: Guochun
authors.initials: G
authors.lastname: Zhou
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
mesh_terms: D000465:Algorithms; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002460:Cell Line; D047630:Depsipeptides / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D025141:Drug Resistance, Fungal / Q000235:genetics; D006801:Humans; D016867:Immunocompromised Host; D007654:Ketoconazole / Q000008:administration & dosage*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009181:Mycoses / Q000188:drug therapy*
chemical_list: D000935:Antifungal Agents; D047630:Depsipeptides; D004338:Drug Combinations; C004456:beauvericin; D007654:Ketoconazole