Synthesis and Evaluation of aza-Novo29 as an Antibiotic Candidate

项目摘要/摘要：aza-Novo 29作为候选抗生素的合成和评价 迫切需要新的抗生素来对抗耐药的革兰氏阳性病原体，如甲氧西林- 耐药金黄色葡萄球菌（MRSA）和耐万古霉素肠球菌（VRE）。这项建议旨在 合成并验证aza-Novo 29作为抗革兰氏阳性病原体新抗生素候选物，其是稳定的 朝向水解。这项提议是基于最近发现的抗生素Novo 29的发现， 有希望的抗生素活性，但在生理pH下水解不稳定。 Novo 29-aza-Novo 29-的大环内酰胺类似物将表现出良好的 抗革兰氏阳性病原体的活性，但在生理pH下不会发生水解。 该提案建立在相关抗生素teixobactin类似物的研究基础上。这些研究 确定了替沙菌素的大环内酰胺类似物不仅耐受大环内酯环的置换， 具有大环内酰胺环，但实际上显示出2-8倍的抗生素活性。该提案还建立在 内酰胺比内酯更耐水解的概念。综合来看，这些观察 表明aza-Novo 29将显示出良好抗菌活性但抗水解。 Novo 29含有非蛋白原性β-羟基天冬酰胺残基。这种β- 羟基天冬酰胺残基是未知。作为所提出的研究的一部分，对β-氨基甲酸酯的立体化学进行了研究。 羟基天冬酰胺残基将通过化学合成并与真实的 Novo29. 有三个具体的目标：（1）开发Novo 29的合成，以便通过以下方式分配其立体化学： 与真实Novo 29的光谱比较和在抗生素活性测定中的并行比较。(2)到 开发氮杂-Novo 29（Novo 29的内酰胺类似物）的合成。(3)为了确定aza-Novo 29是否 对革兰氏阳性病原体具有良好的活性，同时与Novo 29相比具有改善的水解稳定性。 预期的结果是创建aza-Novo 29作为进一步药物治疗的有希望的抗生素候选物。 发展预期aza-Novo 29将表现出良好的抗MRSA和VRE活性，以及抗MRSA和VRE的活性。 在静脉内给药所需条件下的耐水解性。这项研究成果 将通过开发和扩展新发现的抗生素类别来影响抗生素领域， 包括替沙菌素和Novo 29。该项目的成功将为aza的进一步发展铺平道路- Novo 29作为临床前候选抗生素。

Project Summary/Abstract: Synthesis and Evaluation of aza-Novo29 as an Antibiotic Candidate New antibiotics are desperately needed against drug-resistant Gram-positive pathogens, such as methicillin- resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). This proposal seeks to synthesize and validate aza-Novo29 as a new antibiotic candidate against Gram-positive pathogens that is stable toward hydrolysis. The proposal is based on the findings that the recently discovered antibiotic Novo29 shows promising antibiotic activity but is hydrolytically unstable at physiological pH. The central hypothesis that will be tested in the current proposal, is that the macrolactam analogue of Novo29 — aza-Novo29 — will exhibit good activity against Gram-positive pathogens but will not suffer hydrolysis at physiological pH. The proposal builds upon studies of analogues of the related antibiotic teixobactin. These studies have established that a macrolactam analogue of teixobactin not only tolerates replacement of the macrolactone ring with a macrolactam ring, but actually exhibits 2–8-fold greater antibiotic activity. The proposal also builds upon the concept that lactams are far more resistant to hydrolysis than lactones. In combination, these observations suggest that aza-Novo29 will exhibit good antibiotic activity but resist hydrolysis. Novo29 contains a non-proteinogenic β-hydroxyasparagine residue. The stereochemistry of this β- hydroxyasparagine residue is not known. As part of the proposed studies, the stereochemistry of the β- hydroxyasparagine residue will be determined through chemical synthesis and correlation with authentic Novo29. There are three specific aims: (1) To develop a synthesis of Novo29 in order to assign its stereochemistry by spectroscopic comparison to authentic Novo29 and side-by-side comparison in antibiotic activity assays. (2) To develop a synthesis of aza-Novo29, the lactam analogue of Novo29. (3) To determine whether aza-Novo29 has good activity against Gram-positive pathogens, while having improved hydrolytic stability compared to Novo29. The expected outcome is the creation of aza-Novo29 as a promising antibiotic candidate for further drug development. It is expected that aza-Novo29 will exhibit good activity against MRSA and VRE, as well as resistance to hydrolysis under the conditions needed for intravenous administration. The results of this research will impact the field of antibiotics by developing and expanding upon the newly discovered antibiotic class that includes teixobactin and Novo29. The success of this project will pave the way for further development of aza- Novo29 as a preclinical antibiotic candidate.