Synthesis and Evaluation of aza-Novo29 as an Antibiotic Candidate

候选抗生素 aza-Novo29 的合成与评价

• 批准号: 10527638
• 负责人: JAMES S NOWICK
• 金额: $ 21.71万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527638
• 关键词: Antibiotics; Biological Assay; Development; Drug resistance; Evaluation; Exhibits; Hydrolysis; Infection; Lactams; Lactones; Life; Outcome; Patients; Pharmaceutical Preparations; Physiological; Research; Resistance; Side; Testing; Vancomycin resistant enterococcus; analog; base; chemical synthesis; drug candidate; drug development; drug resistant bacteria; fighting; improved; insight; intravenous administration; methicillin resistant Staphylococcus aureus; pathogen; pre-clinical; stereochemistry; success

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.

项目摘要/摘要：AZA-Novo29作为抗生素候选者的合成和评估 迫切需要新的抗生素，以防止耐药的革兰氏阳性病原体，例如甲氧西林 - 抗性金黄色葡萄球菌（MRSA）和万古霉素的肠球菌（VRE）。该提议试图 合成和验证AZA-Novo29作为针对革兰氏阳性病原体的新抗生素候选者 迈向水解。该提案是基于最近发现的抗生素NOVO29显示的发现 有希望的抗生素活性，但在物理pH值下水解不稳定。中心假设将是 在当前的建议中测试的是，Novo29的Macrolactam类似物（Aza-Novo29）将表现出良好 针对革兰氏阳性病原体的活性，但不会在物理pH下进行水解。 该提案建立在对相关抗生素静脉注射的类似物的研究基础上。这些研究有 确定静远亚Xacactin的大分子类似物不仅可以耐受大分子环的替代 带有大酰酰胺环的环，但实际上表现出2-8倍的抗生素活性。该提议也建立在 乳糖比内酯更能抵抗水解的概念。结合这些观察 表明AZA-Novo29将表现出良好的抗生素活性，但可以抵抗水解。 Novo29包含非蛋白蛋白β-羟基股质居住地。该β-的立体化学 羟基甲吡啶居住地尚不清楚。作为拟议研究的一部分，β-的立体化学 羟基氨质居住地将通过化学合成和与真实的相关性确定 Novo29。 有三个具体的目的：（1）开发Novo29的合成，以便通过 与正宗NOVO29和抗生素活性测定中的并排比较的光谱比较。 （2）至 开发了Aza-Novo29，Novo29的Lactam类似物的合成。 （3）确定Aza-Novo29是否具有 与NOVO29相比，对革兰氏阳性病原体的活性良好，同时提高了水解稳定性。 预期的结果是创建AZA-Novo29作为进一步药物的有前途的抗生素候选者 发展。预计Aza-Novo29将对MRSA和VRE表现出良好的活动，以及 在静脉内给药所需的条件下对水解的抗性。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Telexobactin和Novo29。该项目的成功将为进一步发展Aza-铺平道路 NOVO29作为临床前抗生素候选者。