TY - JOUR
T1 - High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections
AU - Zhang, Lixin
AU - Yan, Kezhi
AU - Zhang, Yu
AU - Huang, Ren
AU - Bian, Jiang
AU - Zheng, Chuansen
AU - Sun, Haixiang
AU - Chen, Zhihui
AU - Sun, Nuo
AU - An, Rong
AU - Min, Fangui
AU - Zhao, Weibo
AU - Zhuo, Ying
AU - You, Jianlan
AU - Song, Yongjie
AU - Yu, Zhenyan
AU - Liu, Zhiheng
AU - Yang, Keqian
AU - Gao, Hong
AU - Dai, Huanqin
AU - Zhang, Xiaoli
AU - Wang, Jian
AU - Fu, Chengzhang
AU - Pei, Gang
AU - Liu, Jintao
AU - Zhang, Si
AU - Goodfellow, Michael
AU - Jiang, Yuanying
AU - Kuai, Jun
AU - Zhou, Guochun
AU - Chen, Xiaoping
PY - 2007/3/13
Y1 - 2007/3/13
N2 - 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.
AB - 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.
U2 - 10.1073/pnas.0609370104
DO - 10.1073/pnas.0609370104
M3 - Article
C2 - 17360571
SN - 0027-8424
VL - 104
SP - 4606
EP - 4611
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -