Development of a Novel Class of Gram-Negative Antibiotics that Target Bacterial RNA

开发一类针对细菌 RNA 的新型革兰氏阴性抗生素

• 批准号: 10016075
• 负责人: Stephen Ernest Motika
• 金额: $ 3.96万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2021-03-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016075
• 关键词: 3-Dimensional; Address; Amines; Anabolism; Animal Model; Anti-Bacterial Agents; Antibiotics; Bacterial Antibiotic Resistance; Bacterial Infections; Bacterial RNA; Behavior; Binding; Biological Assay; Biology; Cessation of life; Chemicals; Clinical Data; Collaborations; Collection; Complex; Development; Drug Kinetics; Environment; Escherichia coli; Exhibits; Generations; Genes; Gram-Negative Bacteria; Gram-Positive Bacteria; Growth; Guidelines; Health; Human; Infection; Knowledge; Laboratories; Lead; Membrane; Messenger RNA; Modeling; Modification; Molecular Biology; Multi-Drug Resistance; Mus; Nitrogen; Organism; Outcome; Pathway interactions; Permeability; Pharmaceutical Preparations; Postdoctoral Fellow; Property; Research; Resistance; Resources; Riboflavin; Route; Scientist; Series; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Toxic effect; Training; Translating; Translations; Universities; Work; analog; base; chemical synthesis; clinical candidate; combat; design; drug development; drug resistant pathogen; effective therapy; experience; experimental study; flexibility; graduate student; in vivo; mouse model; novel; pathogen; pathogenic bacteria; pre-clinical; scaffold; screening; small molecule; success

Project Summary Multidrug resistant (MDR) bacterial infections are expected to claim 10 million lives by the year 2050. To combat the rise in MDR bacterial infections, it is crucial that we develop novel classes of antibacterial agents. While progress has been made towards the development of novel classes of antibiotics against Gram-positive bacteria within the past decade, a novel agent for Gram-negative bacteria has not been introduced since 1968. The lack of success regarding the development of Gram- negative bacterial agents is largely attributed to the complex composition of their outer membrane and its impermeability to most small molecules. Moreover, the poor understanding of the physicochemical features that influence accumulation in Gram-negative bacteria underlies the lack of progress in this field. To overcome this obstacle, recent work in our laboratory led to the identification of guidelines for accumulation in E. coli that included the presence of an unencumbered ionizable amine, low flexibility (RB ≤ 5), low 3-dimensionality (Glob ≤ 0.25). In Specific Aim 1, rules for compound accumulation will be applied in the transformation of Ribocil C, a synthetic compound with promising activity against Gram- positive bacteria, into an antibacterial agent with a broadened spectrum of activity. In Specific Aim 2, lead compounds will be evaluated for their translational potential in in vivo studies of toxicity and efficacy. The results from these studies will provide strategies for expanding the chemical diversity of Gram-negative antibiotics, and further define a general blueprint for the conversion of Gram-positive- only compounds into broad-spectrum antibiotics in order to combat emerging resistance. The training environment at UIUC features state-of-the-art facilities and offers many collaborative opportunities with world renowned scientists. The resources and collaborations at this university will aid in accomplishing many of the proposed experiments and designs. The Hergenrother group is also extremely well versed in the fields of chemical synthesis, chemical biology and molecular biology. Any gaps in my research experience and knowledge can be filled through interactions with fellow postdocs and graduate students or through the courses I will be attending during my stay. Overall, the environment in this lab will facilitate the research proposed in the research strategy.

项目摘要 预计到2050年，多药耐药（MDR）细菌感染将夺去1000万生命。 为了打击MDR细菌感染的兴起，至关重要的是，我们开发新的类别 抗菌剂。尽管已经取得了进步 过去十年内针对革兰氏阳性细菌的抗生素，革兰氏阴性剂的新药 自1968年以来一直没有引入细菌。 阴性细菌剂在很大程度上归因于其外膜的复杂组成和 它对大多数小分子的不渗透性。而且，对物理化学化学的不良理解 影响革兰氏阴性细菌积累的特征是缺乏进步的特征 场地。为了克服这一障碍，我们实验室的最新工作导致确定 在大肠杆菌中积聚，包括存在不受限制的电离胺，柔韧性低 （rb≤5），低3维（Glob≤0.25）。在特定的目标1中，复合积累的规则将是 应用于核糖C的转化，核糖C，一种合成化合物，具有有希望的活性对革兰氏的活性 阳性细菌，进入具有拓宽活性谱的抗菌剂。在特定的目标2中， 将评估铅化合物在体内毒性研究中的转化潜力和 效率。这些研究的结果将为扩大化学多样性提供策略 革兰氏阴性抗生素，并进一步定义了革兰氏阳性转化的一般蓝图 仅将化合物分解为广谱抗生素，以打击新兴的耐药性。 UIUC的培训环境功能最先进的设施，并提供许多协作 与世界著名科学家的机会。这所大学的资源和合作将 有助于完成许多提出的实验和设计。 Hergenrother团体也是 非常精通化学合成，化学生物学和分子生物学领域。任何 我的研究经验和知识的差距可以通过与博士后的互动来填补 和研究生或通过我将在逗留期间参加的课程。总体而言， 该实验室的环境将促进研究策略中提出的研究。