Identification of macrocyclic molecules with antibacterial activity

项目摘要 我们开发了一种新的方法来鉴定具有抗菌活性的分子， 快速区分不同的作用机制（MOA）。这种方法， 细菌细胞学分析（BCP），使用定量荧光显微镜， 测量抗生素治疗对单个细胞的影响。抗生素靶向 不同的细胞途径和途径内的不同步骤产生独特的 细胞学概况，允许识别新化合物的可能MOA， 几个小时Linnaeus Bioscience Inc是一家初创公司， 这项技术，并使其在收费的基础上获得服务的制药 工业和科学界。在这个第一阶段的项目中，林奈将筛选 最初开发的6，000多种大环化合物的高度多样化的库 作为激酶抑制剂，以鉴定靶向多药耐药的新分子， (MDR)革兰氏阴性菌。这些独特的化学支架 已经筛选出抗菌化合物，我们的初步数据显示， 富含具有特定MOA的抗菌分子。我们将筛选这些收藏品 针对野生型E.杆菌我们将采用BCP来确定所有命中的可能MOA 在确定优先级之前，并快速消除那些非特异性或不需要的 活性，例如对膜的洗涤剂样作用。我们将反击掩护 针对真核细胞系的细胞毒性以消除高毒性分子。我们将 使用经典的分子遗传学和生物化学方法来识别精确的 分子靶点，并评估对 出现。我们将确定最化学易处理的优先命中系列，并生成 通过药物化学的努力早期领先。这些研究的目的是确定 早期的铅分子，可以进一步发展。这些研究将证明， BCP是一种稳健的基于全细胞成像的方法，能够识别具有以下特征的分子： 在工业规模上的抗菌性能。该平台将广泛用于 按服务收费。

Project Summary We have developed a new method to identify molecules with antibacterial activities that rapidly discriminates between different mechanisms of action (MOA). This approach, bacterial cytological profiling (BCP), uses quantitative fluorescence microscopy to measure the effects of antibiotic treatment on individual cells. Antibiotics that target different cellular pathways and different steps within a pathway generate unique cytological profiles, allowing identification of the likely MOA of new compounds within a few hours. Linnaeus Bioscience Inc. is a start up company founded to commercialize this technology and make it accessible on a fee for service basis to the pharmaceutical industry and the scientific community. During this Phase 1 project, Linnaeus will screen a highly diverse library of more than 6,000 macrocyclic compounds originally developed as kinase inhibitors in order to identify new molecules targeting multidrug resistant (MDR) Gram negative bacteria. This collection of unique chemical scaffolds has never been screened for antibacterial compounds and our preliminary data shows that it is enriched for antibacterial molecules with specific MOAs. We will screen this collection against wild type E. coli. We will employ BCP to identify the likely MOA for all hits before prioritization, and to quickly eliminate those with nonspecific or undesired activities, such as detergent-like effects on the membrane. We will counter screen against eukaryotic cell lines for cytotoxicity to eliminate highly toxic molecules. We will use classical molecular genetic and biochemical approaches to identify the precise molecular target of the prioritized hits, and to evaluate the potential for resistance to emerge. We will identify the most chemically tractable priority hit series and generate early leads through medicinal chemistry efforts. The goal of these studies is to identify early lead molecules that can be developed further. These studies will demonstrate that BCP is a robust whole cell imaging based method capable of identifying molecules with antibacterial properties on an industrial scale. This platform will be made widely available on a fee for service basis.