Synthesis and Studies of a New Family of Antibiotics

项目摘要/摘要：新型抗生素家族的合成与研究 耐药细菌在美国导致200多万人患病，23,000多人死亡 每年，直接社会总成本约为200亿美元，额外的间接社会成本约为 由于生产力下降，损失了350亿美元。尽管迫切需要新的抗生素来对抗日益增长的 由于抗生素耐药细菌的威胁，新抗生素的开发已降至涓涓细流。如果有效 如果不开发新的抗生素，将会有更多的人患病和死亡，这将给人类和经济带来巨大的损失 成本。2015年初，一种新的多肽抗生素被报道，引起了科学界的极大关注 媒体和大众媒体。抗生素teixobactin是一种非核糖体十一肽，含有 大环去脂多肽组和精氨酸类似物耐尿酸地丁或别-耐尿酸地丁。 Teixobactin已经引起了相当大的兴奋，因为它在没有 可检测到的耐药性，对对其他抗生素有耐药性的细菌有效。病原体对 其中有效的teixobactin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--引起葡萄球菌感染的病原体，细菌 肺炎、炭疽和肺结核。替克生对已产生抗药性的细菌有效 对其他抗生素，如耐甲氧西林金黄色葡萄球菌(MRSA)和万古霉素耐药 肠球菌(VRE)。Teixobactin对艰难梭菌也有效，这种细菌已经成为一种特殊的 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 改变治疗抗生素耐药感染的临床做法。理解teixobactin 药效团和获得替克生及其类似物是实现这一承诺的关键。 本提案旨在阐明替克生的药效团，开发替克生的合成方法，以及 发现具有相似药理特性的更简单的类似物。这项工作背后的工作假设 是否有可能仿生合成teixobactin，药效团主要体现在 分子的大环区，从这个区域衍生的更简单的类似物将具有可比性 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 允许创建teixobactin及其类似物的路线。他们将开发一种高效的合成 受保护的耐尿酸地定立体异构体，适用于基于Fmoc的固相肽合成。他们 将评估替克生类似物对革兰氏阳性细菌的活性，并将它们与 替克生。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了解替克生的药效团和合成 获得构建块、teixobactin和teixobactin类似物。

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.