Zhang Lixin, Yan Kezhi, Zhang Yu, Huang Ren, Bian Jiang, Zheng Chuansen, Sun Haixiang, Chen Zhihui, Sun Nuo, An Rong, Min Fangui, Zhao Weibo, Zhuo Ying, You Jianlan, Song Yongjie, Yu Zhenyan, Liu Zhiheng, Yang Keqian, Gao Hong, Dai Huanqin, Zhang Xiaoli, Wang Jian, Fu Chengzhang, Pei Gang, Liu Jintao, Zhang Si, Goodfellow Michael, Jiang Yuanying, Kuai Jun, Zhou Guochun, Chen Xiaoping
Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, China.
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4606-11. doi: 10.1073/pnas.0609370104. Epub 2007 Mar 5.
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.
