Combating Antibiotic Resistance to Aminoglycoside Antibiotics through Chemical Synthesis

越来越多的病原体对最后一道防线抗生素具有耐药性，这导致了公众对新型抗生素研究的新兴趣。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，对氨基糖苷类药物作用方式的广泛研究使得击败这种耐药机制并通过化学合成来对抗它成为可能。现有的氨基糖苷类支架的半合成方法不允许进行必要的化学修饰，并禁止实施结构生物学提供的见解。该项目描述了一个用于发现有效对抗甲基转移酶介导的耐药性的氨基糖苷类药物的全合成平台。该方法的重点是从现成的构建模块中聚合抗生素，并允许进行深层修饰以获得化学上不同的结构。结合微生物测定，可以进行逐步研究和验证结构意义，以克服核糖体细菌耐药性。

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.