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

项目摘要 到2050年，多重耐药(MDR)细菌感染预计将夺走1000万人的生命。 为了抗击耐多药细菌感染的上升，至关重要的是我们开发了新型的 抗菌剂。虽然在开发新的类别的 近十年来抗革兰氏阳性菌的抗生素--一种新的革兰氏阴性菌 自1968年以来，细菌就没有被引入过。葛兰素史克的发展缺乏成功- 阴性细菌很大程度上归因于其外膜的复杂成分和 它对大多数小分子都是不透的。此外，对物理化学的了解也很差 影响革兰氏阴性菌积累的特征是这方面缺乏进展的基础 菲尔德。为了克服这一障碍，我们实验室最近的工作导致确定了 在大肠杆菌中的积累，包括无阻碍的电离胺的存在，灵活性低 (RB≤5)、低三维(GLOB≤0.25)。在具体目标1中，复合累加的规则如下 应用于核素C的转化，这是一种具有良好抗革兰氏活性的合成化合物- 将阳性细菌转化为一种活性范围更广的抗菌剂。在具体目标2中， 将在体内毒性和毒性研究中评估先导化合物的翻译潜力 功效。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，并进一步确定了革兰氏阳性菌转化的总体蓝图- 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 与世界知名科学家合作的机会。这所大学的资源和合作将 帮助完成许多拟议的实验和设计。Hergenrother组也是 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空白可以通过与博士后同行的互动来填补 和研究生，或通过我将在逗留期间参加的课程。总体而言， 本实验室的环境将促进研究策略中提出的研究。

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.