Identification of novel antimicrobials using a live-animal infection model
Identification of novel antimicrobials using a live-animal infection model
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DOI：
10.1073/pnas.0604055103
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发表时间：
2006-07-05
影响因子：
11.1
通讯作者：
Ausubel, Frederick M.
中科院分区：
文献类型：
--
作者：
Moy, Terence I.;Ball, Anthony R.;Ausubel, Frederick M.
抗生素耐药细菌病原体的惊人增长表明需要新的治疗方法来对抗感染。为了发现新的抗菌剂，我们设计了一种筛选方法来鉴定能够促进感染人类机会致病菌粪肠球菌的模型实验室线虫秀丽隐杆线虫存活的化合物。粪肠杆菌在线虫的肠道中定植，形成持续的致命感染。感染的线虫通过抗生素治疗以剂量依赖的方式获救，抗生素治疗显着减少了定植在线虫肠道的细菌数量。为了促进化合物文库的高通量筛选，我们采用了先前开发的基于琼脂的秀丽隐杆线虫- e。粪便感染试验，以便在96孔标准微滴板的液体培养基中进行。我们用这个简单的感染系统筛选了6000种合成化合物和1136种天然产物提取物。我们鉴定出16种化合物和9种提取物能促进线虫的存活。一些化合物和提取物在体外抑制粪肠球菌的生长，但与传统抗生素相比，许多这些化合物的体内有效剂量明显低于体外阻止粪肠球菌生长所需的最低抑制浓度。此外，许多化合物和提取物对体外细菌生长几乎没有影响。我们的研究结果表明，整个动物秀丽隐杆线虫筛选不仅可以识别传统的抗生素，还可以识别靶向细菌毒力或刺激宿主防御的化合物。
The alarming increase of antibiotic-resistant bacterial pathogens points to the need for novel therapeutic approaches to combat infection. To discover novel antimicrobials, we devised a screen to identify compounds that promoted the survival of the model laboratory nematode Caenorhabditis elegans infected with the human opportunistic pathogen Enterococcus faecalis. E. faecalis colonizes the nematode intestinal tract, forming a persistent lethal infection. Infected nematodes were rescued by antibiotic treatment in a dose-dependent manner, and antibiotic treatment markedly reduced the number of bacteria colonizing the nematode intestine. To facilitate high throughput screening of compound libraries, we adapted a previously developed agar-based C. elegans-E. faecalis infection assay so that it could be carried out in liquid medium in standard 96-well microtiter plates. We used this simple infection system to screen 6,000 synthetic compounds and 1,136 natural product extracts. We identified 16 compounds and 9 extracts that promoted nematode survival. Some of the compounds and extracts inhibited E. faecalis growth in vitro, but, in contrast to traditional antibiotics, the in vivo effective dose of many of these compounds was significantly lower than the minimum inhibitory concentration needed to prevent the growth of E. faecalis in vitro. Moreover, many of the compounds and extracts had little or no affect on in vitro bacterial growth. Our findings indicate that the whole-animal G elegans screen identifies not only traditional antibiotics, but also compounds that target bacterial virulence or stimulate host defense.