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High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections
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; zhanglixin@im.ac.cn
2007
Source PublicationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN0027-8424
Volume104Issue:11Pages:4606-4611
AbstractThe 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.
DepartmentChinese 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
KeywordAntifungal Beauvericin Ketoconazole
Subject AreaMultidisciplinary Sciences
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Indexed Bysci
Funding Project海洋地质
WOS IDWOS:000244972700065
Citation statistics
Document Type期刊论文
Identifierhttp://ir.scsio.ac.cn/handle/344004/4504
Collection中科院边缘海地质重点实验室
Corresponding Authorzhanglixin@im.ac.cn
Recommended Citation
GB/T 7714
Zhang, LX,Yan, KZ,Zhang, Y,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, LX.,Yan, KZ.,Zhang, Y.,Huang, R.,Bian, J.,...&zhanglixin@im.ac.cn.(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, LX,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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