Defining Parameters for Compound Accumulation in Gram-Negative Pathogens

定义革兰氏阴性病原体中化合物积累的参数

• 批准号: 9237555
• 负责人: Paul Hergenrother
• 金额: $ 32.95万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237555
• 关键词: Amination; Amines; Anti-Bacterial Agents; Antibiotics; Bacterial Drug Resistance; Biological; Biological Assay; Collection; Computer Analysis; Data; Data Analyses; Development; Drug resistance; Employee Strikes; Escherichia coli; Evaluation; FDA approved; Face; Failure; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Guidelines; Hospitals; Infection; Knowledge; Lead; Libraries; Linezolid; Mediating; Membrane; Natural Products; Nitrogen; Nosocomial Infections; Organism; Outcome; Output; Penetration; Pharmaceutical Preparations; Property; Public Health; Pump; Reporting; Resources; Retrospective Studies; Series; Shapes; Testing; VDAC1 gene; Work; base; design; design and construction; drug candidate; flexibility; member; microorganism; novel; novel drug class; novel therapeutics; pathogen; pleuromutilin; screening; small molecule; trait

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.

项目摘要/摘要 革兰氏阴性细菌病原体引起的感染正在增加医院和非医院 设置。确实，6种“ Eskape”病原体中的4个 - 最近被强调为大多数 医院感染和极难治疗 - 是革兰氏阴性症。新的发展 革兰氏阴性细菌具有高度难以穿透的膜，使抗生素变得复杂 这承认对抗菌剂的内在耐药性明显。没有进步，我们很快就会面对 危机情况，我们目前的抗生素无法再有效地治疗这些感染。虽然是 很明显，迫切需要用于革兰氏阴性感染的新型抗生素，这已经很少 在这方面的进展，自引入新的药物以来已经超过50年了 用于革兰氏阴性病原体。为什么这是？主要原因是没有规则或准则 开发了能够准确地预测革兰氏阴性中复合积累的预测，因此它具有 很难将仅革兰氏阳性药物转化为广谱剂，并且不可能创建 大量因革兰氏阴性积累而有偏见的化合物。我们一直在工作 定义小分子的物理特征，使它们可以积聚在大肠杆菌中。在 重要的初步结果我们已经评估了180种潜水员的化合物，以使它们积累的能力 在大肠杆菌中；使用数据的复杂计算分析，我们已经开始辨别 控制大肠杆菌中复合积累的物理特征，我们已经使用了这些准则 将革兰氏阳性的抗生素转化为具有许多革兰氏阴性活性的一种 病原体。现在，我们建议进一步了解大肠杆菌中的复合积累 （特别是关于孔蛋白渗透和泵介导的外排），并扩展这些准则 到其他革兰氏阴性病原体。我们还将使用指南转换重要的FDA批准 目前仅对革兰氏阳性细菌有效到衍生物有效的抗生素，这也是 活跃于革兰氏阴性生物。最后，我们将使用指南设计和构建 收集了数千种化合物，所有这些化合物都在革兰氏阴性含量中积累了很大的偏见 细菌。这项工作的重大输出包括对化合物类型的基本理解 积累在革兰氏阴性细菌中，可用于发现新颖的准则 抗菌。