Platforms for the Synthesis of Bacterial Protein Synthesis Inhibitors

项目概要/摘要 仅引入了两种新结构的抗生素，例如达托霉素和利奈唑胺 近50年来推向市场。新型抗生素的缺乏并不是因为缺乏新的化学物质，而是因为缺乏新的化学物质。 事实上，每年都会发现数十甚至数百种具有抗菌活性的分子，但 其中大多数不适合用作人类疗法。此外，许多抗生素 市场上的产品具有不良特性（例如毒性、化学不稳定性、代谢负担），阻碍了 医生不得雇用他们。大多数这些分子都具有高度的结构复杂性 使改善其特性的药物化学努力变得复杂化。我们的实验室致力于解决这个问题 通过开发模块化策略来组装结构复杂的抗生素类别来应对挑战 尚未发挥其治疗潜力。与许多全合成提案不同，我们的主要目标是 不开发合成天然产物的方法（尽管这可以通过我们的方法来完成） 方法），而是使用它们的结构体系结构来指导新结构类的开发。 在运营的头两年中，我们开发了一种模块化、可扩展的链霉素合成方法 抗生素（J. Am. Chem. Soc. 2017，doi：10.1021/jacs.7b08577），我们已经取得了重大进展 迈向兰卡西丁抗生素的实际合成。以这些初步结果为基础，五年内 NIGMS MIRA 资金将支持基于这些类别的结构新颖的疗法的开发 改善了理化性质、扩大了活性谱并增强了抗病毒活性 多重耐药细菌菌株。化学和生物创新将促进这一追求 广泛的适用性。我们还提出了一种我们认为结合诱导杂交的方法 其用途将超出核糖体靶向抗生素的应用范围。我们的努力将通过战略来实现 合作以实现我们类似物的结合相互作用的晶体学表征（与Prof. Yury Polikanov，UIC）并评估候选抗生素对广泛细菌的功效 病原体，包括许多多重耐药菌株（与 Dean Shinabarger 博士合作，Micromyx）。 该研究计划意义重大，因为它有可能扩大化学反应的前沿， 促进结构生物学的发现，并解决紧迫的未满足的医疗需求。

Project Summary/Abstract Only two new structural classes of antibiotics, exemplified by daptomycin and linezolid, have been introduced to the market in the past 50 years. This dearth of novel antibiotics is not due to lack of new chemical matter; indeed, dozens or even hundreds of molecules with antimicrobial activity are discovered annually, but the majority of these are not suitable for deployment as human therapeutics. Additionally, many of the antibiotics on the market have undesirable properties (e.g., toxicity, chemical instability, metabolic liabilities) that deter physicians from employing them. The high degree of structural complexity present in most of these molecules complicates medicinal chemistry efforts to improve their properties. Our laboratory seeks to address this challenge by developing modular strategies for the assembly of structurally complex classes of antibiotics that have not yet reached their potential as therapeutics. Unlike many total synthesis proposals, our primary goal is not to develop methods for the synthesis of natural products (although this can be accomplished with our approach), but rather to use their structural architectures to guide the development of new structural classes. During our first 2 years in operation, we have developed a modular, scalable synthesis of streptogramin antibiotics (J. Am. Chem. Soc. 2017, doi: 10.1021/jacs.7b08577), and we have made significant headway towards a practical synthesis of lankacidin antibiotics. With these preliminary results as groundwork, five years of NIGMS MIRA funding will enable the development structurally novel therapeutics based on these classes that have improved physicochemical properties, broader spectra of activity, and increased activity against multidrug-resistant strains of bacteria. This pursuit will be facilitated by chemical and biological innovations with broad applicability. We also propose a method for binding-induced hybridization of therapeutics that we believe will find use beyond the application to ribosome-targeting antibiotics. Our efforts will be enabled by strategic collaborations to enable crystallographic characterization of the binding interactions of our analogs (with Prof. Yury Polikanov, UIC) and to evaluate the efficacy of antibiotic candidates against a broad panel of bacterial pathogens, including many multi-drug resistant strains (with Dr. Dean Shinabarger, Micromyx). This research program is significant because it has the potential to expand the frontiers of chemical reactivity, to facilitate discoveries in structural biology, and to address an urgent unmet medical need.