Combating Antibiotic Resistance to Aminoglycoside Antibiotics through Chemical Synthesis

通过化学合成对抗氨基糖苷类抗生素的耐药性

• 批准号: 392481159
• 负责人: Dr. Sven Hildebrandt
• 金额: --
• 依托单位: Department of Chemistry and Chemical Biology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/392481159?language=en
• 关键词: Combating; Antibiotic; Resistance; Aminoglycoside; Antibiotics

The increasing number of pathogens resistant to last-line-of-defense antibiotics has led to a renewed public interest in research for novel antibiotics. Resistance to aminoglycoside antibiotics conferred by ribosomal methyltransferase enzymes is a new threat reported within the last decade. However, extensive research on the mode of action of aminoglycosides makes it feasible to defeat this resistance mechanism and combat it with chemical synthesis. Existing semi-synthetic approaches to aminoglycoside scaffolds do not allow necessary chemical modifications and prohibit the implementation of insights delivered by structural biology. This project describes a total synthesis platform for the discovery of aminoglycosides effective against methyltransferase mediated resistance. The approach focuses on the convergent assembly of antibiotics from readily available building blocks and allows deep-seated modifications to obtain chemically diverse structures. In combination with microbiological assays, a step-wise investigation and validation of the structural implications to overcome ribosomal bacterial resistance can be conducted.

越来越多的病原体对最后一道防线抗生素具有耐药性，这使得公众对新型抗生素的研究重新产生了兴趣。核糖体甲基转移酶对氨基糖苷类抗生素的耐药性是近十年来报道的一种新的威胁。然而，对氨基糖苷的作用方式的广泛研究使得突破这种耐药机制并通过化学合成来对抗它成为可能。现有的氨基糖苷支架的半合成方法不允许进行必要的化学修饰，并且禁止实施结构生物学提供的见解。本项目描述了一个全合成平台，发现氨基糖苷有效对抗甲基转移酶介导的抗性。该方法侧重于从现成的构建块集中组装抗生素，并允许深层修饰以获得化学上不同的结构。结合微生物学分析，可以对克服核糖体细菌耐药性的结构意义进行逐步调查和验证。