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 到2050年，多重耐药（MDR）细菌感染预计将夺去1000万人的生命。 为了对抗MDR细菌感染的上升，我们开发新型的 抗菌剂虽然在开发新的分类方面取得了进展， 革兰氏阳性菌的抗生素在过去的十年中，一种新的代理革兰氏阴性 自1968年以来，细菌没有被引入。由于缺乏对Gram的开发， 阴性细菌因子主要归因于其外膜的复杂组成， 它对大多数小分子的不渗透性。此外，对物理化学的理解不足 影响革兰氏阴性菌中积累的特征是这方面缺乏进展的基础。 领域为了克服这一障碍，我们实验室最近的工作导致了以下指导方针的确定： E.大肠杆菌，其中包括存在一个未受阻碍的电离胺，低灵活性 (RB≤ 5），低三维度（Glob ≤ 0.25）。在具体目标1中，复合累积的规则将是 应用于核糖核酸C的转化，核糖核酸C是一种具有抗革兰氏阴性菌活性的合成化合物， 阳性细菌转化为具有广谱活性的抗菌剂。在具体目标2中， 将在体内毒性研究中评价先导化合物的转化潜力， 功效这些研究的结果将为扩大化学多样性提供战略， 革兰氏阴性抗生素，并进一步确定了革兰氏阳性转化的一般蓝图- 只有将化合物转化为广谱抗生素，才能对抗新出现的耐药性。 UIUC的培训环境具有最先进的设施，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 帮助完成许多提出的实验和设计。Hergenrother集团也是 在化学合成、化学生物学和分子生物学领域非常精通。任何 我的研究经验和知识的差距可以通过与其他博士后的互动来填补 和研究生或通过课程，我将参加在我逗留期间。总体看 这个实验室的环境将促进研究策略中提出的研究。