One size fits all: The semi-synthesis of new undecaprenol analogues for the study of multiple undecaprenyl-processing enzymes

一刀切：半合成新型十一异戊二烯醇类似物，用于研究多种十一异戊烯基加工酶

• 批准号: EP/S015892/1
• 负责人: Stephen Cochrane
• 金额: $ 27.5万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS015892%2F1
• 关键词: size; fits; semi; synthesis; new

Antibacterial resistance is a major threat to human health and there is a pertinent need for new antimicrobial targets. Bacteria produce several glycopolymers that are vital to their survival, including peptidoglycan, which is a key component of the bacterial cell wall required for structural integrity. The bacterial cell wall is targeted by many clinically used antibiotics, such as penicillin and vancomycin. Glycopolymer biosynthesis involves several key glycolipid intermediates, all of which are linked to the cell membrane by the molecule undecaprenol. The enzymes that process undecaprenol-linked biomolecules are hot antibiotic targets, as they are unique to bacteria. However, detailed studies on these enzymes and the high-throughput screening of possible inhibitors has been limited due to the lack of suitable probes to monitor their activity. An understanding of enzyme mechanism is a vital pre-requisite to the rationale design of inhibitors. This project aims to develop new labelled analogues of undecaprenol, which will be used to study several novel antibiotic targets and provide a method for the high-throughput screening of potential antibiotic candidates.

抗生素耐药性是人类健康的主要威胁，因此迫切需要新的抗微生物靶标。细菌产生几种对其生存至关重要的糖聚合物，包括肽聚糖，肽聚糖是结构完整性所需的细菌细胞壁的关键组分。许多临床使用的抗生素，如青霉素和万古霉素，都以细菌细胞壁为靶点。糖聚合物的生物合成涉及几种关键的糖脂中间体，所有这些中间体都通过十一萜醇分子与细胞膜连接。处理十一烯醇连接的生物分子的酶是热门的抗生素靶标，因为它们是细菌所特有的。然而，由于缺乏合适的探针来监测其活性，对这些酶的详细研究和可能的抑制剂的高通量筛选受到限制。了解酶的作用机理是合理设计抑制剂的重要前提。该项目旨在开发新的标记的十一肾上腺素类似物，其将用于研究几种新的抗生素靶标，并为高通量筛选潜在的抗生素候选物提供方法。

项目成果

Optimizations of Lipid II Synthesis: An Essential Glycolipid Precursor in Bacterial Cell Wall Synthesis and a Validated Antibiotic Target

脂质 II 合成的优化：细菌细胞壁合成中必需的糖脂前体和经过验证的抗生素靶点

• DOI: 10.3762/bxiv.2023.49.v1
• 发表时间: 2023
• 作者: Karak M

Targeting membrane-bound bacterial cell wall precursors: a tried and true antibiotic strategy in nature and the clinic.

靶向膜结合细菌细胞壁前体：自然界和临床中经过验证的真实抗生素策略。

• DOI: 10.1039/d3cc01070h
• 发表时间: 2023
• 期刊: Chemical communications (Cambridge, England)
• 作者: Buijs NP