Defining Parameters for Compound Accumulation in Gram-Negative Pathogens

项目总结/摘要 革兰氏阴性细菌病原体引起的医院和非医院感染呈上升趋势 设置.事实上，6种“ESKAPE”病原体中有4种--最近强调是大多数疾病的罪魁祸首 医院感染和非常难以治疗的-是革兰氏阴性菌。发展新 革兰氏阴性菌具有高度不可穿透的细胞膜， 其赋予对抗菌剂显著的内在抗性。如果没有进步，我们很快就会面临 我们目前的抗生素已不能有效治疗这些感染。虽然 很明显，迫切需要用于革兰氏阴性菌感染的新型抗生素， 在这方面取得了进展，并且自从引入一类新药物以来已有50多年 革兰氏阴性病原体为什么会这样呢？一个主要原因是，没有规则或指导方针， 开发，使准确预测化合物的积累，在革兰氏阴性，因此， 很难将仅革兰氏阳性药物转化为广谱药物， 偏向于革兰氏阴性积累的化合物的大量集合。我们一直致力 以确定小分子的物理化学特征，使它们能够在E.杆菌在 重要的初步结果，我们已经评估了超过180种不同的化合物的积累能力， 在大肠大肠杆菌;使用复杂的计算分析的数据，我们已经开始辨别， 控制化合物在E.大肠杆菌，我们使用这些指导方针， 将仅革兰氏阳性抗生素转化为对许多革兰氏阴性抗生素也具有活性的抗生素， 病原体我们现在建议进一步了解E.杆菌 （特别是关于孔蛋白渗透和泵介导的外排），并扩展这些指南 与其他革兰氏阴性病原体的区别我们还将使用该指南来转换FDA批准的重要内容 目前仅对革兰氏阳性菌有效的抗生素转化为衍生物， 对革兰氏阴性菌有效。最后，我们将使用我们的指南来设计和构建一个 数千种化合物的集合，所有这些化合物都严重偏向于在革兰氏阴性菌中积累 细菌这项工作的重要成果包括对化合物类型的基本了解 在革兰氏阴性菌中积累的，以及用于发现新的 抗菌药物。

Project Summary/Abstract Infections caused by Gram-negative bacterial pathogens are on the rise in hospital and non-hospital settings. Indeed 4 of the 6 “ESKAPE” pathogens – recently highlighted as responsible for the majority of hospital infections and being exceedingly difficult to treat – are Gram-negatives. The development of new antibiotics is complicated by the fact that Gram-negative bacteria have a highly impenetrable membrane that confers significant intrinsic resistance to antibacterial agents. Without advances, we will soon face a crisis situation whereby our current antibiotics can no longer effectively treat these infections. Although it is clear that novel antibiotics for Gram-negative infections are desperately needed, there has been minimal progress in this regard, and it has been over 50 years since a new class of drugs have been introduced for Gram-negative pathogens. Why is this? A chief reason is that no rules or guidelines have been developed that enable the accurate prediction of compound accumulation in Gram-negatives, thus it has been difficult to convert Gram-positive-only drugs into broad-spectrum agents, and impossible to create large collections of compounds that are biased for Gram-negative accumulation. We have been working to define the physicochemical features of small molecules that allow them to accumulate in E. coli. In important preliminary results we have assessed >180 diverse compounds for their ability to accumulate in E. coli; using a sophisticated computation analysis of the data, we have begun to discern the physicochemical traits that govern compound accumulation in E. coli, and we have used these guidelines to convert a Gram-positive-only antibiotic into one that also has activity against many Gram-negative pathogens. We now propose to gain a further understanding of compound accumulation in E. coli (especially with respect to porin penetration and pump-mediated efflux), and to extend these guidelines to other Gram-negative pathogens. We will also use the guidelines to convert important FDA-approved antibiotics that are currently only effective against Gram-positive bacteria into derivatives that are also active against Gram-negative organisms. Finally, we will use our guidelines to design and construct a collection of thousands of compounds all of which are heavily biased for accumulation in Gram-negative bacteria. Significant outputs of this work include a fundamental understanding of the types of compounds that accumulate in Gram-negative bacteria, and actionable guidelines to be used to discover novel antibacterials.