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Biosynthetic engineering approaches to the creation of novel enacyloxin IIa analogues

创造新型 enacyloxin IIa 类似物的生物合成工程方法

基本信息

批准号：
2590900
负责人：
金额：
--
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2590900
关键词：
Biosynthetic engineering approaches creation novel

项目摘要

"Antibiotics are an essential part of modern medicine, but antimicrobial resistance (AMR) is rapidly neutralising their effectiveness. There is thus an urgent need to develop new antibiotics to overcome the health threat posed by AMR. This is particularly the case for Acinetobacter baumannii, which has recently been identified by the World Health Organisation as one of three "critical priority" pathogens for which new antibiotics are urgently needed to overcome resistance to current treatments. Enacyloxin IIa is an antibiotic produced by Burkholderia species with potent activity against Acinetobacter baumannii, including antibiotic-resistant clinical isolates, that blocks proteinsynthesis by allosterically inhibiting EF-Tu. To optimise enacyloxin for clinical use, analogues are needed to illuminate its structure-activity relationship and improve its aqueous solubility and chemical stability. However, the structural complexity of enacyloxin IIa makes such analogues challenging to produce via chemical synthesis. This project aims to exploit extensive insights into enacyloxin IIa biosynthesis generated by the Challis group over more than a decade to produce novel analogues with improved solubility and stability.These analogues will enable a more complete assessment of the potential of enacyloxin IIa to be developed into a into a useful antibiotic for the treatment of infections caused by A. baumannii."

“抗生素是现代医学的重要组成部分，但抗菌素耐药性(AMR)正在迅速抵消它们的有效性。因此，迫切需要开发新的抗生素来克服AMR构成的健康威胁。鲍曼不动杆菌尤其如此，它最近被世界卫生组织确定为三种“关键优先”病原体之一，迫切需要新的抗生素来克服对当前治疗的耐药性。Enacylosin IIa是一种由Burkholderia种产生的抗生素，对鲍曼不动杆菌具有很强的活性，包括对抗生素耐药的临床分离株，它通过变构抑制EF-Tu来阻断蛋白质的合成。为了优化纳西洛辛的临床应用，需要类似物来阐明其构效关系，并改善其在水中的溶解性和化学稳定性。然而，由于其结构的复杂性，使得这类类似物很难通过化学合成来生产。该项目旨在利用Challis小组在十多年的时间里对纳西洛辛IIa生物合成的广泛见解，以生产具有更好的溶解性和稳定性的新型类似物。这些类似物将使人们能够更全面地评估纳西洛辛IIa被开发成一种治疗鲍曼不动杆菌感染的有用抗生素的潜力。“