Defining Parameters for Compound Accumulation in Gram-Negative Pathogens

项目摘要/摘要 由革兰氏阴性细菌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-最近被强调为导致大多数 医院感染和极其难以治疗-是革兰氏阴性菌。新技术的发展 由于革兰氏阴性细菌有一层高度不透膜，这使得抗生素变得复杂。 这赋予了对抗菌剂显著的内在抗药性。如果没有进步，我们很快就会面临 我们目前的抗生素不再能有效治疗这些感染的危机局面。尽管它 很明显，治疗革兰氏阴性感染的新抗生素是迫切需要的，但已经有了很少的 在这方面取得了进展，自推出一类新药物以来，已经有50多年了 革兰氏阴性病原体。这是为什么？一个主要原因是没有规则或指导方针 开发出了能够准确预测革兰氏阴性菌中化合物积累的技术，因此它 将仅革兰氏阳性药物转化为广谱药物是困难的，而且不可能创造 对革兰氏阴性菌积累有偏见的化合物的大量集合。我们一直在工作 确定小分子的物理化学特征，使它们能够在大肠杆菌中积累。在……里面 我们评估了180种不同化合物的累积能力的重要初步结果 在大肠杆菌中；使用对数据的复杂计算分析，我们已经开始辨别 控制化合物在大肠杆菌中积累的物理化学特征，我们使用了这些指南 将一种仅对革兰氏阳性的抗生素转换为对许多革兰氏阴性菌也有活性的抗生素 病原体。我们现在建议对化合物在大肠杆菌中的积累有进一步的了解。 (特别是关于孔蛋白渗透和泵介导的外排)，并扩展这些指南 对其他革兰氏阴性病原体。我们还将使用该指南将FDA批准的重要 将目前仅对革兰氏阳性菌有效的抗生素转化为也 对革兰氏阴性菌有积极作用。最后，我们将使用我们的指导原则来设计和构建 收集数以千计的化合物，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 在革兰氏阴性细菌中积累的物质，以及用于发现新的可操作指南 抗菌药。

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.