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

蜜蜂是人类最重要的生命体之一。芽胞形成细菌幼虫拟青霉是美国污浊病的病原菌，也是世界性的病原菌。对P.幼虫基因组的测序有助于鉴定四类化合物的次生代谢物基因簇：铁载体杆状杆菌蛋白、脂肽派尼拉文、三肽七伐他星和多肽/聚酮杂化化合物派尼拉米星。将在该项目内进行的研究致力于以下方面的研究：1)预苯胺霉素的前药物激活，2)青霉素生产者的耐药机制，3)硫代酯酶(TE)非依赖的生物合成终止机制。此外，我们的目的是加深对次生代谢产物在P.幼虫对蜜蜂幼虫致病作用的理解。该项目的另一部分包括青霉素的全合成和衍生物的合成，以帮助确定抗菌和抗真菌生物活性的分子靶标和作用模式。

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.