High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections.
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.
Zhang
Lixin
L
Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, China. zhanglixin@im.ac.cn
Yan
Kezhi
K
Zhang
Yu
Y
Huang
Ren
R
Bian
Jiang
J
Zheng
Chuansen
C
Sun
Haixiang
H
Chen
Zhihui
Z
Sun
Nuo
N
An
Rong
R
Min
Fangui
F
Zhao
Weibo
W
Zhuo
Ying
Y
You
Jianlan
J
Song
Yongjie
Y
Yu
Zhenyan
Z
Liu
Zhiheng
Z
Yang
Keqian
K
Gao
Hong
H
Dai
Huanqin
H
Zhang
Xiaoli
X
Wang
Jian
J
Fu
Chengzhang
C
Pei
Gang
G
Liu
Jintao
J
Zhang
Si
S
Goodfellow
Michael
M
Jiang
Yuanying
Y
Kuai
Jun
J
Zhou
Guochun
G
Chen
Xiaoping
X
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*
D000935:Antifungal Agents; D047630:Depsipeptides; D004338:Drug Combinations; C004456:beauvericin; D007654:Ketoconazole