Muraymycin-type nucleoside antibiotics: studies on target interaction and on bacterial cellular uptake

由于新出现的病原菌对已建立的抗微生物剂具有抗性，因此迫切需要开发新型抗生素。理想情况下，这种新型抗微生物化合物应显示新的或尚未开发的作用模式。核苷类抗生素，也包括muraymycins，是抑制细菌膜蛋白MraY的天然产物。MraY是肽聚糖生物合成的细胞内部分的关键酶，因此对于细菌细胞壁的组装是必不可少的。有几种化学全合成Muraymycin类似物的路线以及一些关于结构-活性关系的数据。然而，许多分子的相互作用的muraymycins及其类似物与MraY的细节尚未阐明。基于最近报道的X-射线晶体结构的MraY与村霉素配体，它是设想合成新的类似物，并研究其生物学特性。这些化合物将进一步深入了解配体-靶标相互作用，也可能显示出更高的生物学效力。这些研究将通过对胞内作用的muraymycin类似物的细菌细胞摄取的研究来补充。总体而言，该研究项目将从根本上有助于对muraymycins及其类似物的抗生素作用的分子理解。所获得的结果将使得能够设计合成容易获得的简化的村霉素类似物，其结合了对MraY的强抑制效力和足够的细胞摄取，从而代表了用于抗微生物药物开发的潜在候选化合物。

Due to emerging pathogenic bacteria with resistances against established antimicrobial agents, the development of novel antibiotics is urgently needed. Ideally, such novel antimicrobial compounds should display new or yet unexploited modes of action. Nucleoside antibiotics, which also include muraymycins, are natural products inhibiting the bacterial membrane protein MraY. MraY is a key enzyme in the intracellular part of peptidoglycan biosynthesis and therefore essential for the assembly of the bacterial cell wall.There are several routes for the chemical total synthesis of muraymycin analogues as well as some data on structure-activity relationships available. Nevertheless, many molecular details of the interaction of muraymycins and their analogues with MraY are not elucidated yet. Based on a recently reported X-ray crystal structure of MraY with a muraymycin ligand, it is envisioned to synthesise novel analogues and to study their biological properties. These compounds will furnish further insights into the ligand-target interaction and might also display increased biological potency. These investigations will be complemented by studies on the bacterial cellular uptake of the intracellularly acting muraymycin analogues.Overall, this research project will fundamentally contribute to the molecular understanding of the antibiotic action of muraymycins and their analogues. The obtained results will enable the design of synthetically readily accessible simplified muraymycin analogues combining strong inhibitory potency towards MraY with sufficent cellular uptake, thus representing potential candidate compounds for antimicrobial drug development.