A Novel Screen for Antibacterials that Are Non-Toxic to Mammals

 描述（由申请人提供）：迫切需要新的治疗剂来治疗抗微生物剂耐药性革兰氏阴性菌。历史上，抗生素是使用全细菌在筛选中鉴定的。在过去的20年里，有针对细菌分子的密集的生化筛选，这种方法经常识别出在病原体或哺乳动物宿主中具有显著屏障的化合物，包括无法进入或留在宿主或病原体细胞内，被宿主或病原体破坏，或宿主细胞毒性。因此，我们开发了一种定量的、基于图像的高内容筛选，该筛选排除了具有不良性质的化合物，因为它使用了在哺乳动物细胞内生长的完整的、有毒的细菌。我们建议使用这种筛选来确定针对非必需细菌毒力因子的治疗方法，并对抗生素耐药细菌有效。

 DESCRIPTION (provided by applicant): There is a critical need for novel therapeutics to treat antimicrobial-resistant Gram-negative bacteria. Historically, antibiotics were identified in screen using whole bacteria. Over the past 20 years, there has instead been intensive biochemical screening that targets bacterial molecules, an approach that has often identified compounds with significant barriers in either the pathogen or the mammalian host, including an inability to enter or remain within host or pathogen cells, destruction by the host or pathogen, or host cytotoxicity. We have therefore developed a quantitative, image-based high content screen that excludes compounds with undesirable properties because it uses whole, virulent, bacteria growing within mammalian cells. We propose to use this screen to identify therapeutics that target nonessential bacterial virulence factors and will be effective against antimicrobial-resistant bacteria.