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Synthesis and Studies of a New Family of Antibiotics

新抗生素家族的合成与研究

基本信息

批准号：
9231356
负责人：
JAMES S NOWICK
金额：
$ 17.35万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231356
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 Pharmacology Phase Productivity Property Publishing Reporting Research Resistance Resistance development Route Scanning Solid Staphylococcus aureus Stereoisomer Streptococcus Streptococcus pneumoniae Structure Tuberculosis Vancomycin resistant enterococcus Work 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

项目摘要

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：一个新的抗生素家族的合成和研究抗生素耐药性细菌在美国造成200多万人患病，23，000多人死亡每年，直接的社会总成本约为200亿美元，额外的间接社会成本约为 350亿美元是因为生产力下降。尽管迫切需要新的抗生素来对抗日益增长的由于抗药性细菌的威胁，新抗生素的开发已经下降到涓涓细流。如果有效如果不开发出新的抗生素，更多的人将患病和死亡，成本在2015年初，报道了一种新的肽抗生素，在科学界和医学界都引起了极大的关注。媒体和大众媒体。抗生素替沙菌素是一种非核糖体十一肽，大环缩酚酸肽基团和精氨酸类似物曲拉西定或别曲拉西定。 Teixobactin已经引起了相当大的兴奋，因为它可以杀死革兰氏阳性细菌，可检测到的耐药性，并对耐其他抗生素的细菌有效。病原体其中具有活性的替沙菌素包括金黄色葡萄球菌、肺炎链球菌和其它链球菌，炭疽杆菌和结核分枝杆菌--导致葡萄球菌感染的病原体，肺炎炭疽和肺结核Teixobactin对已经产生耐药性的细菌有效其他抗生素，如耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素肠球菌（VRE）。Teixobactin也对艰难梭菌有效，艰难梭菌已成为一种特殊的抗生素。其他抗生素引起的问题。如果teixobactin或teixobactin类似物实现了它们的承诺，改变耐药感染治疗的临床实践。了解teixobactin 药效团和获得teixobactin和类似物是实现这一承诺的关键。该提案旨在阐明teixobactin的药效团，开发teixobactin的合成，发现具有相似药理学性质的更简单的类似物。这项工作背后的工作假设是，仿生合成teixobactin是可能的，药效团主要体现在分子的大环区域，并且衍生自该区域的更简单的类似物将具有可比的药理学特性在执行这个项目时，PI和他的研究小组将开发一种合成的该路线允许产生teixobactin和类似物。他们将开发一种有效的合成方法，本发明提供了适合用于基于Fmoc的固相肽合成的受保护的西拉西啶立体异构体。他们将评估teixobactin类似物对革兰氏阳性菌的活性，并将其与替沙菌素他们将制备和研究teixobactin的衍生物，以阐明teixobactin的药效团。这些研究的结果将是更好地理解teixobactin药效团和合成药物。获得结构单元、teixobactin和teixobactin类似物。