Platforms for the Synthesis of Bacterial Protein Synthesis Inhibitors

项目摘要/摘要 只有两种新的结构类抗生素被引入，例如达托霉素和利奈唑胺。 在过去的50年里，它被推向市场。缺乏新型抗生素并不是因为缺乏新的化学物质； 事实上，每年都有数十种甚至数百种具有抗菌活性的分子被发现，但 其中大多数不适合作为人类疗法部署。此外，许多抗生素 市场上有不良的特性(例如，毒性、化学不稳定性、新陈代谢易感性) 医生不会雇用他们。这些分子中的大多数都存在高度的结构复杂性 使改善其性能的药物化学努力复杂化。我们的实验室试图解决这个问题 通过开发模块化策略来组装结构复杂的抗生素类来实现挑战 还没有发挥出它们作为治疗学的潜力。与许多全合成方案不同，我们的主要目标是 不开发合成天然产品的方法(尽管这可以通过我们的 方法)，而是使用它们的结构体系结构来指导新的结构类的开发。 在我们运营的头两年里，我们开发了一种模块化的、可扩展的链菌素合成法 抗生素(J.Am化学。SoC。2017年，DOI：10.1021/Jacs.7b08577)，我们已经取得了重大进展 一种实用的兰卡西丁抗生素的合成。以这些初步结果为基础，五年 NIGMS Mira的资金将使基于这些类别的结构新疗法的开发成为可能 它们具有改善的物理化学性质，更广泛的活性光谱，并增强了对 具有多重耐药性的细菌菌株。这一追求将通过化学和生物创新来促进， 适用范围广。我们还提出了一种结合诱导杂交的方法，我们认为 将在核糖体靶向抗生素的应用之外找到用途。我们的努力将得到战略的支持 合作，以使我们的类似物的结合相互作用的结晶学表征(与教授。 Yury Polikanov，UIC)，并评估候选抗生素对广泛的细菌群的疗效 病原体，包括许多耐多药菌株(与Micromyx的Dean Shinabarger博士)。 这项研究计划意义重大，因为它有可能扩大化学反应的前沿， 以促进结构生物学的发现，并解决一个紧急的未得到满足的医疗需求。

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.