Platforms for the Synthesis of Bacterial Protein Synthesis Inhibitors

项目概要/摘要 只有两个新的抗生素结构类别，例如达托霉素和利奈唑胺，已被引入 在过去的50年里，新型抗生素的缺乏并不是因为缺乏新的化学物质; 事实上，每年都发现数十种甚至数百种具有抗微生物活性的分子， 这些药物中的大多数不适合用作人类治疗剂。此外，许多抗生素 具有不希望的性质（例如，毒性，化学不稳定性，代谢负债），阻止 医生雇用他们。这些分子的高度结构复杂性 使改善其性质的药物化学努力复杂化。我们的实验室试图解决这个问题 通过开发用于组装结构复杂的抗生素类别的模块化策略， 还没有发挥出它们作为治疗剂的潜力。与许多全合成提案不同，我们的主要目标是 不开发天然产物的合成方法（尽管这可以通过我们的方法来实现）。 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。 在我们运营的前2年里，我们开发了链阳菌素的模块化、可扩展合成 抗生素（J. Am. 2017，doi：10.1021/jacs.7b08577），我们已经取得了重大进展 lankacidin抗生素的实际合成。以这些初步成果为基础， NIGMS MIRA的资金将使开发基于这些类别的结构新颖的治疗方法成为可能 其具有改善的物理化学性质、更宽的活性谱和增加的抗 多重耐药菌株化学和生物创新将促进这一追求， 广泛的适用性。我们还提出了一种结合诱导杂交的治疗方法，我们相信， 将在核糖体靶向抗生素之外找到用途。我们的努力将通过战略性的 合作，使我们的类似物的结合相互作用的晶体学表征（与教授。 Yury Polikanov，UIC），并评估抗生素候选物对一组广泛的细菌的功效。 病原体，包括许多多药耐药菌株（与Dean Shinabarger博士，Micromyx）。 这项研究计划意义重大，因为它有可能扩大化学反应性的前沿， 以促进结构生物学的发现，并解决迫切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.