热门
High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections
文献类型：期刊论文
| 作者 | Zhang, Lixin; Yan, Kezhi; Zhang, Yu; Huang, Ren; Bian, Jiang; Zheng, Chuansen; Sun, Haixiang; Chen, Zhihui; Sun, Nuo; An, Rong |
| 刊名 | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
 |
| 出版日期 | 2007-03-13 |
| 卷号 | 104期号:11页码:4606-4611 |
| ISSN号 | 0027-8424 |
| 关键词 | Antifungal Beauvericin Ketoconazole |
| DOI | 10.1073/pnas.0609370104 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| 学科主题 | Multidisciplinary Sciences |
| URL标识 | 查看原文 |
| 语种 | 英语 |
| WOS记录号 | WOS:000244972700065 |
| 公开日期 | 2010-11-18 |
| 源URL | [http://ir.qdio.ac.cn/handle/337002/1714]  |
| 专题 | 海洋研究所_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. |
入库方式： OAI收割
来源：海洋研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。