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学科主题: Multidisciplinary Sciences
题名: High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections
作者: Zhang, LX ; Yan, KZ ; Zhang, Y ; Huang, R ; Bian, J ; Zheng, CS ; Sun, HX ; Chen, ZH ; Sun, N ; An, R ; Min, FG ; Zhao, WB ; Zhuo, Y ; You, JL ; Song, YJ ; Yu, ZY ; Liu, ZH ; Yang, KQ ; Gao, H ; Dai, HQ ; Zhang, XL ; Wang, J ; Fu, CZ ; Pei, G ; Liu, JT ; Zhang, S ; Goodfellow, M ; Jiang, YY ; Kuai, J ; Zhou, GC ; Chen, XP
通讯作者: zhanglixin@im.ac.cn
关键词: antifungal ; beauvericin ; ketoconazole
刊名: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
发表日期: 2007
卷: 104, 期:11, 页:4606-4611
收录类别: sci
部门归属: Chinese Acad Sci, Inst Microbiol, Beijing 100080, Peoples R China; Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Beijing 510663, Peoples R China; Chinese Acad Sci, S China Sea Inst Oceanol, Beijing 510301, Peoples R China; SynerZ Pharmaceut Inc, Lexington, MA 02421 USA; Guangdong Lab Anim Mo0nitoring Inst, Beijing 510301, Peoples R China; Chinese Acad Sci, Grad Sch, Beijing 100049, Peoples R China; Chinese Acad Sci, Inst Oceanol, Qingdao 266071, Peoples R China; Univ Newcastle Upon Tyne, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England; Second Mil Med Univ, Dept Pharmacol, Cambridge, MA 02140 USA; Wyeth Res, Cambridge, MA 02140 USA
项目归属: 海洋地质
摘要: 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 approximate to 20,000 microbial extracts, 12 hits were identified with broadspectrum 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.
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WOS记录号: WOS:000244972700065
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内容类型: 期刊论文
URI标识: http://ir.scsio.ac.cn/handle/344004/4504
Appears in Collections:中科院边缘海地质重点实验室_期刊论文

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Recommended Citation:
Zhang, LX; Yan, KZ; Zhang, Y; Huang, R; Bian, J; Zheng, CS; Sun, HX; Chen, ZH; Sun, N; An, R; Min, FG; Zhao, WB; Zhuo, Y; You, JL; Song, YJ; Yu, ZY; Liu, ZH; Yang, KQ; Gao, H; Dai, HQ; Zhang, XL; Wang, J; Fu, CZ; Pei, G; Liu, JT; Zhang, S; Goodfellow, M; Jiang, YY; Kuai, J; Zhou, GC; Chen, XP.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,2007,104(11):4606-4611
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