Enzyme-instructed nanoscale assemblies for killing multidrug resistant bacteria

酶指导的纳米级组装体用于杀死多重耐药细菌

• 批准号: 9422669
• 负责人: Bing Xu
• 金额: $ 24.38万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-03 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9422669
• 关键词: Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Bacteria; Binding; Biochemical Reaction; Catalysis; Cations; Centers for Disease Control and Prevention (U.S.); Cessation of life; Charge; Clinical; Communicable Diseases; Development; Disease Outbreaks; Drug resistance; Enterococcus; Enzymes; Equilibrium; Event; Goals; Growth; Healthcare; Hydrolysis; In Situ; Infection; Lead; Length; Ligands; Microbial Biofilms; Modernization; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mutation; Peptides; Prevalence; Property; Public Health; Research; Resistance; Role; Side; Societies; Superbug; Surface; United States; Vancomycin; Work; antimicrobial; antimicrobial drug; bacterial resistance; bactericide; base; beta-Lactamase; beta-Lactams; design; drug development; drug resistant bacteria; improved; methicillin resistant Staphylococcus aureus; molecular assembly/self assembly; nanofiber; nanoscale; novel; novel strategies; novel therapeutics; pathogen; pathogenic bacteria; peptide B; protein aminoacid sequence; receptor; receptor binding; scaffold; self assembly

ABSTRACT The increasing prevalence of drug-resistance among pathogenic bacteria to common antibiotics has become one of the most pressing global healthcare problems in modern society. There is an urgent need for novel antimicrobial agents against multidrug resistant (MDR) bacteria. Because the major cause of resistance is beta-lactamase (a bacteria-specific enzyme) to degrade antibiotics, the proposed work will turn the cause of resistance to the event of killing the bacteria. That is, this research will develop the precursors that are responsive to beta-lactamase for in-situ (i.e., on the surface of bacteria) formation of nanoscale assemblies that kill MDR bacteria. The goal of this work is to explore enzyme-instructed self-assembly—that is, the integration of enzymatic catalysis and molecular self-assembly—as a paradigm-shifting approach for the discovery and early development of novel therapies for treating infections caused by drug resistant bacteria. This proposal is both hypothesis and design driven. We hypothesize that enzyme-instructed self-assembly, as a unique way to localize the nanoscale assemblies of cationic peptides onto bacteria, will kill MDR bacteria. Our past results—beta-lactamase instructing self-assembly of peptides, self-assembled nanofibers of ultrashort cationic peptides inhibiting biofilms, enzyme-instructed self-assembly inhibiting bacterial growth, and multivalent antibiotics inhibiting MDR bacteria—strongly support the hypothesis. To validate the hypothesis, we will design cationic peptides that self-assemble upon the action of beta-lactamase, characterize the physiochemical properties of the peptides and their assemblies, and assess the antibacterial activities of the nanoscale assemblies against MDR bacteria. Specifically, we will evaluate 1) the effects of charge balance of the precursors, 2) the effects of side chain length of the cationic peptides, and 3) the effects of peptide sequence of the cationic peptides on the nanoscale assemblies of cationic peptides for killing MDR bacteria. By designing, synthesizing, and characterizing the β-lactam containing precursors of cationic peptides and evaluate the antibacterial activities of the corresponding assemblies of the cationic peptides against MDR bacteria, we anticipate that this research will improve fundamental understanding of antimicrobial therapy, provide guiding principles to design antibacterial agents, and ultimately lead to an unprecedented approach of antibacterial drug development that integrates enzymatic reactions and molecular self-assembly.

摘要 病原菌对常用抗生素的耐药性日益普遍， 成为现代社会最紧迫的全球医疗保健问题之一。迫切需要 针对多药耐药（MDR）细菌的新型抗菌药物。因为抵抗的主要原因 是β-内酰胺酶（一种细菌特异性酶）降解抗生素，拟议的工作将把原因， 抵抗杀死细菌的事件。也就是说，这项研究将开发出 响应于β-内酰胺酶的原位（即，在细菌的表面上）形成纳米级组件 能杀死耐多药细菌这项工作的目标是探索酶指导的自组装，即， 整合酶催化和分子自组装-作为一种范式转变的方法， 发现和早期开发用于治疗由耐药细菌引起的感染的新疗法。 这个建议是假设和设计驱动的。我们假设，酶指导的自组装，如 将阳离子肽的纳米级组装体定位到细菌上的独特方法将杀死MDR细菌。 我们过去的成果-β-内酰胺酶指导自组装肽，自组装纳米纤维的超短 抑制生物膜的阳离子肽，抑制细菌生长的酶指导的自组装，和 抑制MDR细菌的多价抗生素-强烈支持该假设。为了验证这个假设，我们 将设计在β-内酰胺酶作用下自组装的阳离子肽，表征 肽及其组装体的理化性质，并评估肽及其组装体的抗菌活性。 纳米组装对抗MDR细菌。具体而言，我们将评估1）电荷平衡的影响， 前体的影响，2）阳离子肽的侧链长度的影响，和3）肽的影响， 用于杀死MDR细菌的阳离子肽纳米级组装体上的阳离子肽的序列。 通过设计、合成和表征含有β-内酰胺的阳离子肽前体， 评价了阳离子多肽组装体对MDR的抗菌活性 细菌，我们预计这项研究将提高抗菌治疗的基本理解， 提供设计抗菌剂的指导原则，并最终导致前所未有的方法， 整合酶反应和分子自组装的抗菌药物开发。

项目成果

Diglycine Enables Rapid Intrabacterial Hydrolysis for Activating Anbiotics against Gram-negative Bacteria.

• DOI: 10.1002/anie.201905230
• 发表时间: 2019-06
• 期刊: Angewandte Chemie
• 作者: Jiaqing Wang;Deani L. Cooper;Wenjun Zhan;Difei Wu;Hongjian He;Shenghuan Sun;S. Lovett;Bing Xu