| 查看: 161 | 回复: 1 | |||
| 当前主题已经存档。 | |||
bhz_2001铁杆木虫 (著名写手)
|
[交流]
Antibiotic Halts Lipid Synthesis
|
||
|
Small-molecule natural product is a potent antibiotic with a novel target Celia Arnaud A new antibiotic that targets an enzyme in the fatty acid synthesis pathway in bacteria could become a weapon against antibiotic resistance, according to a report from a team of researchers at Merck (Nature 2006, 441, 358). The scientists declined to reveal Merck's current plans for the compound, but they say it remains the subject of intense investigation. "This target is not totally new, but this compound is exceptionally promising," says Robert E. W. Hancock, a microbiologist at the University of British Columbia, Vancouver. "We desperately need novel drugs to counteract the alarming increase in resistance." The Merck team, which was led by biologist Jun Wang, structural biologist Stephen M. Soisson, and natural products chemist Sheo B. Singh, found the new molecule, called platensimycin, by fishing it out of a library of 250,000 natural product extracts. The molecule is produced by Streptomyces platensis, a bacterium isolated from a South African soil sample. Platensimycin inhibits an enzyme in fatty acid synthesis called FabF, one of two enzymes that catalyze the addition of two-carbon units to the growing fatty acid chain. "FabF is one of the critical enzymes in the pathway," Soisson says. "It's essential and it's present in all bacteria that we know of." Other natural products are known to affect this enzyme, but none is used therapeutically. Finding new targets is particularly important for addressing antibiotic resistance, Wang says. "Working on existing targets, you can improve efficacy, but most likely you cannot overcome target resistance. A novel target will help with this," he says. The researchers custom-designed a screening assay to search for a FabF inhibitor in the extracts. They engineered a strain of Staphylococcus aureus to produce antisense RNA that gives them tight control of the amount of FabF produced. "By doing that, you make the cell more sensitive to the presence of an antimicrobial that targets that specific gene product," Soisson says. "You increase your sensitivity for detecting things in natural product extracts that may be present in extremely low concentrations." In addition, because the screen is target-based, "you get a preliminary hint at mechanism," he says. TeamWork Singh (from left), Soisson, and Wang led the team that discovered platensimycin.Structural studies were challenging because platensimycin inhibits a short-lived acylated enzyme intermediate in which a structural change allows the antibiotic to block the active site. The transience of the target's conformation was "a big surprise," Soisson says. The researchers obtained crystal structures by making mutant proteins that mimic the acylated enzyme intermediate. In mice, platensimycin eliminates S. aureus infection. In addition, the antibiotic is effective in cell-based assays against a number of gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant enterococci. Because the drug is rapidly cleared from the body, it requires continuous intravenous delivery. Christopher T. Walsh, a biochemist at Harvard Medical School who studies antibiotic mechanisms, says, "It remains to be seen if simplified versions of this natural product will be optimized leads, but this natural product should make the fatty acid synthesis pathway a higher priority" as an antibiotic target. Chemical & Engineering News ISSN 0009-2347 Copyright © 2006 American Chemical Society |
回复此楼» 猜你喜欢
是不是现在考博都是推荐制？或者是已经内定了？还有通过考试招博士的学校吗？
已经有39人回复
-
农产品中农药监测的免疫传感器的疑问
已经有0人回复
-
药物学论文润色/翻译怎么收费?
已经有194人回复
-
纳米传感器监测农药残留的疑惑
已经有0人回复
-
谁有人卫版 《毒理学基础》第七版书籍
已经有0人回复
-
[求助] 流式死活染 & 单细胞门控设置被质疑，如何优化并解释？
已经有1人回复
-
蛋白稳定性实验与功能实验不一致
已经有11人回复
-
第4年了，马上40了，可能我与国基确实无缘吧。。。
已经有12人回复
-
26有没有老师想收做定量药理的学生啊
已经有2人回复
-
2026年申博药学专业
已经有1人回复
-
26考博申请 学or专
已经有15人回复
0.5
 |
2楼2006-05-26 15:43:19