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

 描述(由申请人提供)：迫切需要新的疗法来治疗抗菌素耐药的革兰氏阴性细菌。在历史上，抗生素是用整个细菌在筛查中鉴定出来的。在过去的20年里，取而代之的是以细菌分子为目标的密集的生化筛选，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，宿主或病原体的破坏，或宿主的细胞毒性。因此，我们开发了一种基于图像的定量高含量屏幕，它排除了具有不良特性的化合物，因为它使用的是在哺乳动物细胞中生长的完整的、有毒的细菌。我们建议使用这一筛选来确定针对非必要细菌毒力因子的治疗药物，并将有效地对抗抗菌素耐药性细菌。

 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.