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

doi:10.1073/pnas.0609370104

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	High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections
	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 ; Zhang, LX, Chinese Acad Sci, Inst Microbiol, Beijing 100080, Peoples R China
	2007-03-13
发表期刊	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN	0027-8424
卷号	104 期号:11 页码:4606-4611
文章类型	Article
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.; 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.
关键词	Antifungal Beauvericin Ketoconazole
学科领域	Multidisciplinary Sciences
DOI	10.1073/pnas.0609370104
URL	查看原文
收录类别	SCI
语种	英语
WOS记录号	WOS:000244972700065
引用统计	被引频次：192[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.qdio.ac.cn/handle/337002/1713
专题	实验海洋生物学重点实验室
通讯作者	Zhang, LX, Chinese Acad Sci, Inst Microbiol, Beijing 100080, Peoples R China
作者单位	1.Chinese Acad Sci, Inst Microbiol, Beijing 100080, Peoples R China 2.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Beijing 510663, Peoples R China 3.Chinese Acad Sci, S China Sea Inst Oceanol, Beijing 510301, Peoples R China 4.SynerZ Pharmaceut Inc, Lexington, MA 02421 USA 5.Guangdong Lab Anim Mo0nitoring Inst, Beijing 510301, Peoples R China 6.Chinese Acad Sci, Grad Sch, Beijing 100049, Peoples R China 7.Chinese Acad Sci, Inst Oceanol, Qingdao 266071, Peoples R China 8.Univ Newcastle Upon Tyne, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England 9.Second Mil Med Univ, Dept Pharmacol, Cambridge, MA 02140 USA 10.Wyeth Res, Cambridge, MA 02140 USA
推荐引用方式 GB/T 7714	Zhang, Lixin,Yan, Kezhi,Zhang, Yu,et al. High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2007,104(11):4606-4611.
APA	Zhang, Lixin.,Yan, Kezhi.,Zhang, Yu.,Huang, Ren.,Bian, Jiang.,...&Zhang, LX, Chinese Acad Sci, Inst Microbiol, Beijing 100080, Peoples R China.(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),4606-4611.
MLA	Zhang, Lixin,et al."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(2007):4606-4611.

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