Synthesis and Evaluation of aza-Novo29 as an Antibiotic Candidate

项目摘要/摘要：抗生素候选化合物Aza-Novo29的合成与评价 对耐药的革兰氏阳性病原体，如甲氧西林，迫切需要新的抗生素。 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 抗革兰氏阳性菌稳定的新型候选抗生素Aza-Novo29的合成与验证 朝着水解的方向发展。这项提议是基于最近发现的抗生素Novo29的发现 具有良好的抗菌活性，但在生理pH下不稳定。中心假设将是 在目前的提案中测试的是Novo29的大内酰胺类似物-aza-Novo29-将表现出良好的 对革兰氏阳性病原体的活性，但在生理pH下不会发生水解。 该提案建立在对相关抗生素替克生类似物的研究基础上。这些研究已经 确定了替考巴坦的大内酰胺类似物不仅能耐受大内酯环的替换 具有大内酰胺环，但实际上显示出2-8倍的抗生素活性。该提案还建立在 内酰胺类比内酯类更耐水解的概念。总而言之，这些观察结果 提示Aza-Novo29将表现出良好的抗菌活性，但耐水解。 Novo29含有一个非蛋白来源的β-羟基天冬酰胺残基。这个β的立体化学- 羟天冬酰胺残留量尚不清楚。作为拟议研究的一部分，β的立体化学- 羟基天冬酰胺残留量将通过化学合成和与真品的相关性来测定 11月29日。 有三个具体目标：(1)开发Novo29的合成，以便通过以下方法确定其立体化学 与正品Novo29的光谱比较和抗生素活性测定中的并列比较。(2)至 开发氮杂-Novo29的合成方法，Novo29的内酰胺类似物。(3)确定Aza-Novo29是否有 对革兰氏阳性病原体具有良好的活性，同时与Novo29相比，具有更好的水解稳定性。 预期的结果是创造出Aza-Novo29作为未来药物的有希望的抗生素候选 发展。预计Aza-Novo29对耐甲氧西林金黄色葡萄球菌和VRE以及 在静脉给药所需的条件下耐水解。这项研究的结果 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 包括替克生和Novo29。该项目的成功将为Aza的进一步发展铺平道路。 Novo29作为临床前抗生素候选。

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.