Synthesis and Studies of a New Family of Antibiotics

新抗生素家族的合成与研究

• 批准号: 9014830
• 负责人: JAMES S NOWICK
• 金额: $ 19.85万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014830
• 关键词: Advanced Development; Alanine; Amino Acids; Anthrax disease; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Arginine; Attention; Bacillus anthracis; Bacteria; Bacterial Pneumonia; Binding; Biological; Biomimetics; Cessation of life; Clostridium difficile; Depsipeptides; Development; Diphosphates; Drops; Family; Financial cost; Gram-Positive Bacteria; Human; Infection; Molecular; Mycobacterium tuberculosis; N-terminal; Outcome Study; Peptide Antibiotics; Peptide Synthesis; Phase; Productivity; Property; Publishing; Reporting; Research; Resistance; Resistance development; Route; Scanning; Solid; Staphylococcus aureus; Stereoisomer; Streptococcus; Streptococcus pneumoniae; Structure; Thinking; Tuberculosis; Vancomycin resistant enterococcus; Work; abstracting; analog; bacterial resistance; base; chemical synthesis; clinical practice; cost; drug resistant bacteria; fighting; improved; insight; killings; methicillin resistant Staphylococcus aureus; muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; novel therapeutics; pathogen; pharmacophore; stereochemistry; tool

Project Summary/Abstract: Synthesis and Studies of a New Family of Antibiotics Antibiotic-resistant bacteria cause more than 2 million illnesses and more than 23,000 deaths in the US each year, with direct overall societal costs of about $20 billion and additional indirect societal costs of about $35 billion due to lost productivity. Although there is a desperate need for new antibiotics to fight the growing threat of antibiotic-resistant bacteria, the development of new antibiotics has dropped to a trickle. If effective new antibiotics are not developed, many more people will be sickened and die, at great human and financial cost. At the beginning of 2015 a new peptide antibiotic was reported, with great attention in both the scientific press and the popular press. The antibiotic, teixobactin is a non-ribosomal undecapeptide containing a macrocyclic depsipeptide group and the arginine analogue enduracididine or allo-enduracididine. Teixobactin has generated considerable excitement because it kills gram-positive bacteria without detectable resistance and is effective against bacteria that are resistant to other antibiotics. Pathogens against which teixobactin is active include Staphylococcus aureus, Streptococcus pneumoniae and other Streptococci, Bacillus anthracis, and Mycobacterium tuberculosis -- the pathogens that cause staph infections, bacterial pneumonia, anthrax, and tuberculosis. Teixobactin is effective against bacteria that have developed resistance to other antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Teixobactin is also effective against Clostridium difficile, which has become a particular problem as a result of other antibiotics. If teixobactin or teixobactin analogues realize their promise, they will change clinical practice for the treatment of antibiotic-resistant infections. Understanding the teixobactin pharmacophore and having access teixobactin and analogues is essential to realizing this promise. This proposal seeks to elucidate the pharmacophore of teixobactin, develop a synthesis of teixobactin, and discover simpler analogues with similar pharmacological properties. The working hypotheses behind this work are that a biomimetic synthesis of teixobactin is possible, that the pharmacophore is embodied primarily in the macrocyclic region of the molecule, and that simpler analogues derived from this region will have comparable pharmacological properties. In executing this project, the PI and his research group will develop a synthetic route that permits the creation of teixobactin and analogues. They will develop an efficient synthesis of protected enduracididine stereoisomers suitable for use in Fmoc-based solid-phase peptide synthesis. They will assess the activity of the teixobactin analogues against gram-positive bacteria and compare them to teixobactin. They will prepare and study derivatives of teixobactin to elucidate the teixobactin pharmacophore. The outcome of these studies will be a better understanding of the teixobactin pharmacophore and synthetic access to building blocks, teixobactin, and teixobactin analogues.

项目摘要/摘要：新的抗生素家族的合成和研究 抗生素耐药细菌在美国导致超过200万疾病和23,000多人死亡 每年，直接的总体社会成本约为200亿美元，额外的间接社会费用约为 350亿美元由于生产力损失。尽管迫切需要新的抗生素与成长 抗生素耐药菌的威胁，新抗生素的发展已滴落。如果有效 新的抗生素没有开发，在伟大的人类和财务上，更多的人会生病和死亡 成本。 2015年初 媒体和流行媒体。抗生素Teixobactin是一种非核糖体，含有A 大环皮肽组和精氨酸类似物耐酰胺或异源性尿素。 Teixobactin引起了极大的兴奋，因为它会杀死革兰氏阳性细菌 可检测的耐药性，对对其他抗生素有抗性的细菌有效。病原体反对 哪种teixobactin活性包括金黄色葡萄球菌，肺炎链球菌和其他链球菌 炭疽芽孢杆菌和结核分枝杆菌 - 引起葡萄球菌感染的病原体，细菌 肺炎，炭疽和结核病。 Teixobactin对产生抗性的细菌有效 到其他抗生素，例如耐甲氧西林金黄色葡萄球菌（MRSA）和抗性霉素 肠球菌（VRE）。 Teixobactin也对艰难梭菌也有效，这已成为一种特定的 由于其他抗生素而导致的问题。如果Teixobactin或Teixobactin类似物意识到他们的诺言，他们将 改变治疗抗生素耐药感染的临床实践。了解Teixobactin 药效团并具有访问Teixobactin和类似物对于实现这一诺言至关重要。 该提案旨在阐明Teixobactin的药片，形成Teixobactin的合成和 发现具有相似药理特性的简单类似物。这项工作背后的工作假设 是否有可能将Teixobactin的仿生合成，使药效团主要体现在 分子的大环区域，从该区域得出的更简单的类似物将具有可比的 药理特性。在执行该项目时，PI及其研究小组将开发合成 允许创建Teixobactin和类似物的路线。他们将开发有效的合成 受保护的耐酰胺类立体异构体适合用于基于FMOC的固相肽合成。他们 将评估Teixobactin类似物对革兰氏阳性细菌的活性，并将其比较 Teixobactin。他们将准备和研究Teixobactin的衍生物，以阐明Teixobactin Pharmacocotore。 这些研究的结果将更好地理解Teixobactin Pharmacocotore和Synthetic 访问构建块，Teixobactin和Teixobactin类似物。