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

由于新出现的致病菌对现有的抗微生物药物具有耐药性，迫切需要开发新的抗生素。理想情况下，这种新型抗菌化合物应该显示出新的或尚未开发的作用模式。核苷类抗生素，也包括穆拉霉素，是抑制细菌膜蛋白MraY的天然产物。MraY是细胞内肽聚糖生物合成的关键酶，因此对细菌细胞壁的组装至关重要。有几种化学全合成穆霉素类似物的途径以及一些结构-活性关系的数据。然而，许多分子细节的相互作用的muraymycin和他们的类似物与MraY尚未阐明。基于最近报道的含有鼠霉素配体的MraY的x射线晶体结构，设想合成新的类似物并研究它们的生物学特性。这些化合物将进一步深入了解配体与靶标的相互作用，并可能显示出更高的生物效力。这些研究将通过对细胞内作用的穆拉霉素类似物的细菌细胞摄取的研究来补充。总的来说，本研究项目将从根本上促进对muraymycin及其类似物的抗生素作用的分子理解。所获得的结果将使设计易于合成的简化穆拉霉素类似物成为可能，这些类似物结合了对MraY的强抑制效力和足够的细胞摄取，从而代表了抗菌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.