High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections

Lixin Zhang, Kezhi Yan, Yu Zhang, Ren Huang, Jiang Bian, Chuansen Zheng, Haixiang Sun, Zhihui Chen, Nuo Sun, Rong An, Fangui Min, Weibo Zhao, Ying Zhuo, Jianlan You, Yongjie Song, Zhenyan Yu, Zhiheng Liu, Keqian Yang, Hong Gao, Huanqin DaiXiaoli Zhang, Jian Wang, Chengzhang Fu, Gang Pei, Jintao Liu, Si Zhang, Michael Goodfellow, Yuanying Jiang, Jun Kuai, Guochun Zhou, Xiaoping Chen

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish
    Pages (from-to)4606-11
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume104
    Issue number11
    DOIs
    Publication statusPublished - 13 Mar 2007

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  • Cite this

    Zhang, L., Yan, K., Zhang, Y., Huang, R., Bian, J., Zheng, C., Sun, H., Chen, Z., Sun, N., An, R., Min, F., Zhao, W., Zhuo, Y., You, J., Song, Y., Yu, Z., Liu, Z., Yang, K., Gao, H., ... Chen, X. (2007). High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections. Proceedings of the National Academy of Sciences of the United States of America, 104(11), 4606-11. https://doi.org/10.1073/pnas.0609370104