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：新抗生素家族的合成与研究在美国，抗生素耐药性细菌导致超过 200 万人患病和超过 23,000 人死亡每年，直接总体社会成本约为 200 亿美元，额外间接社会成本约为生产力损失造成 350 亿美元损失。尽管迫切需要新的抗生素来对抗日益增长的细菌由于抗生素耐药性细菌的威胁，新抗生素的开发已逐渐减少。如果有效的话如果不开发出新的抗生素，将会有更多的人患病和死亡，这将耗费巨大的人力和财力成本。 2015年初，一种新型肽类抗生素被报道，引起科学界和学术界的高度关注。媒体和大众媒体。抗生素 teixobactin 是一种非核糖体十一肽，含有大环缩酚肽基团和精氨酸类似物enduracididine或allo-enduracididine。 Teixobactin 引起了相当大的兴奋，因为它可以杀死革兰氏阳性细菌而不需要可检测到的耐药性，并且可有效对抗对其他抗生素有耐药性的细菌。病原体针对 teixobactin 具有活性的包括金黄色葡萄球菌、肺炎链球菌和其他链球菌，炭疽杆菌和结核分枝杆菌——引起葡萄球菌感染、细菌感染的病原体肺炎、炭疽病和肺结核。 Teixobactin 可有效对抗已产生耐药性的细菌其他抗生素，例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 对艰难梭菌也有效，该菌已成为一种特殊的其他抗生素导致的问题。如果 teixobactin 或 teixobactin 类似物实现了他们的承诺，他们将改变抗生素耐药感染治疗的临床实践。了解替克巴汀药效基团和获得替克巴汀及其类似物对于实现这一承诺至关重要。该提案旨在阐明 teixobactin 的药效团，开发 teixobactin 的合成方法，并发现具有相似药理学特性的更简单的类似物。这项工作背后的工作假设 Teixobactin 的仿生合成是可能的，药效团主要体现在分子的大环区域，并且从该区域衍生的更简单的类似物将具有可比较的药理特性。在执行这个项目时，PI和他的研究小组将开发一种合成的允许产生teixobactin和类似物的路线。他们将开发一种有效的合成方法受保护的enduracididine立体异构体，适用于基于Fmoc的固相肽合成。他们将评估 teixobactin 类似物对抗革兰氏阳性菌的活性，并将其与替克巴汀。他们将制备和研究泰克巴汀衍生物，以阐明泰克巴汀药效团。这些研究的结果将是更好地了解替肖巴汀药效团和合成获得构建模块、teixobactin 和 teixobactin 类似物。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epidemiologic studies of group 9 pneumococci in terms of protein type and 9N versus 9V capsular type.

第 9 组肺炎球菌在蛋白质类型和 9N 与 9V 荚膜类型方面的流行病学研究。

DOI：
发表时间：
1991-04
期刊：
影响因子：
0
作者：
Waltman, W D;Gray, B M;Svanborg, C;Facklam, R;Briles, D E
通讯作者：
Briles, D E

Elucidation of the Teixobactin Pharmacophore.

Teixobactin 药效团的阐明。

DOI：
10.1021/acschembio.6b00295
发表时间：
2016-07-15
期刊：
ACS chemical biology
影响因子：
4
作者：
Yang H;Chen KH;Nowick JS
通讯作者：
Nowick JS

Alanine scan reveals modifiable residues in teixobactin.

丙氨酸扫描揭示了 teixobactin 中的可修饰残基。

DOI：
10.1039/c7cc03415f
发表时间：
2017-10-12
期刊：
Chemical communications
影响因子：
4.9
作者：
Chen KH;Le SP;Han X;Frias JM;Nowick JS
通讯作者：
Nowick JS

Pneumococcal surface protein A (PspA) is serologically highly variable and is expressed by all clinically important capsular serotypes of Streptococcus pneumoniae.

肺炎球菌表面蛋白 A (PspA) 在血清学上具有高度可变性，并且由所有临床上重要的肺炎链球菌荚膜血清型表达。

DOI：
发表时间：
1990-10
期刊：
影响因子：
3.1
作者：
Crain, M J;Waltman 2nd, W D;Turner, J S;Yother, J;Talkington, D F;McDaniel, L S;Gray, B M;Briles, D E
通讯作者：
Briles, D E

Pneumococcal surface protein A is expressed in vivo, and antibodies to PspA are effective for therapy in a murine model of pneumococcal sepsis.

肺炎球菌表面蛋白 A 在体内表达，PspA 抗体可有效治疗肺炎球菌脓毒症小鼠模型。