Interdisciplinary studies on non-ribosonmally synthesised secondary metabolites from Paenibacillus larvae

蜜蜂是人类最重要的生命资源之一。芽孢形成细菌幼虫类芽孢杆菌是美洲幼虫腐臭病的病原体，也是世界范围内发生的病原体。幼虫的基因组测序有助于鉴定四类化合物的次级代谢物基因簇：铁载体bacillibactin，脂肽paenilarvin，三肽sevadicin和肽/聚酮混合化合物paenilamicin。该项目中进行的研究致力于研究1）阿替尼霉素的前药活化，2）阿替尼霉素生产者的耐药机制和3）生物合成的硫酯酶（TE）非依赖性终止机制。进一步加深对次生代谢产物在幼虫疫霉致病中的作用的认识。该项目的另一部分包括paenilamycins的全合成和衍生物的合成，以帮助确定分子靶点和抗菌和抗真菌生物活性的作用方式。

The honey bee is one of the most important lifestock to human. The spore forming bacterium Paenibacillus larvae is the causative agent of the american foulbrood and a worldwide occurring pathogen. Sequencing of the genome of P. larvae facilitated the identification of secondary metabolite gene clusters of four compound classes: the siderophore bacillibactin, the lipopeptide paenilarvin, the tripeptide sevadicin and the peptide/polyketide-hybrid compound paenilamicin. The research to be performed within the project is dedicated to the investigation of 1) the prodrug-activation of prepaenilamicin, 2) the mechanism of resistance of the paenilamicin producer and 3) the thioesterase (TE)-independant termination mechanism of the biosynthesis. Furthermore we aim at a deepened understanding of the function of secondary metabolites in the pathogenesis of P. larvae on the laervae of the honeybee. A further part of the project comprises the total synthesis of paenilamycins and the synthesis of derivatives in order to aid in the determination of the molecular target and the mode of action excerting antibacterial and antifungal bioactivity.