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

蜜蜂是人类最重要的生命来源之一。芽孢形成细菌芽孢杆菌的幼虫是美国的致病因子和世界范围内发生的病原体。通过对P.幼虫基因组的测序，鉴定出4类化合物的次生代谢产物基因簇：铁载体bacillibactin、脂肽paenilarvin、三肽sevadicin和多肽/聚酮杂交化合物paenilamicin。该项目将致力于研究1)pre - paenilamicin的药物前激活，2)paenilamicin生产者的耐药机制，以及3)生物合成的不依赖于硫酯酶（TE）的终止机制。此外，我们的目的是加深了解次生代谢物在P.幼虫对蜜蜂幼虫的发病机制中的作用。该项目的另一部分包括paenilamycin的总合成和衍生物的合成，以帮助确定分子靶点和作用模式，其中包括抗菌和抗真菌生物活性。

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.