Screening for myxobacterial natural products : new structures, biosynthesis, and contributions to a comprehensive screening workflow

摘要

The rapid emergence of antibiotic resistance enforces the search for new pharmaceutically relevant compounds. Here, especially natural products from microbial sources are becoming important once again. In this regard, the present work deals with the characterization of new myxobacterial natural products and their biosynthesis alongside with the development of an improved method for the chemical analysis of complex biological samples.This thesis covers the isolation of two natural products, pellasoren and microsclerodermin, both derived from the crude extracts of the genome-sequenced strain Sorangium cellulosum So ce38. Full structure elucidation of pellasoren led to the identification of its biosynthetic gene cluster and the underlying biosynthesis. Furthermore, as a result of a comprehensive screening project, several terrestrial myxobacteria were unambiguously identified as producers of the marine natural product microsclerodermin. This finding resembles one of the few known cases of an identical metabolite derived from terrestrial and marine habitats. The isolation and subsequent characterization of two new derivatives from different strains resulted in the identification of two biosynthetic gene clusters. As a consequence, structural differences of the derivatives could be rationalized based on slight variations within both clusters.In addition, a method to optimize the informational content of LC-MS/MS data was developed. Statistical evaluation of LC-MS data facilitated the identification of signals linked to bacterial metabolism, which were subjected to MS/MS analysis irrespective of their intensity. This methodology was successfully applied to identify the novel lipothiazole compound class in S. cellulosum So ceGT47.