Strong Antibiotic Activity of the Myxocoumarin Scaffold in vitro and in vivo.

The increasing emergence of resistances against established antibiotics is a substantial threat to human health. The discovery of new compounds with potent antibiotic activity is thus of utmost importance. Within this work, we identify strong antibiotic activity of the natural product myxocoumarin B from Stigmatella aurantiaca MYX-030 against a range of clinically relevant bacterial pathogens, including clinical isolates of MRSA. A focused library of structural analogs was synthesized to explore initial structure-activity relationships and to identify equipotent myxocoumarin derivatives devoid of the natural nitro substituent to significantly streamline synthetic access. The cytotoxicity of the myxocoumarins as well as their potential to cure bacterial infections in vivo was established using a zebrafish model system. Our results reveal the exceptional antibiotic activity of the myxocoumarin scaffold and hence its potential for the development of novel antibiotics.

Synthesis and initial biological evaluation of myxocoumarin B.

The myxocoumarins A and B from Stigmatella aurantiaca MYX-030 are natural products featuring unusual nitro- and long-chain alkyl substitution. While myxocoumarin A was shown to exhibit strong antifungal properties, the antifungal potential of myxocoumarin B was not yet assessed due to low production titers during initial isolation. We therefore developed a total synthesis of myxocoumarin B that involves a late-stage Pd-catalyzed nitration of the coumarin core. The availability of synthetic material facilitated the initial evaluation of the bioactivity of myxocoumarin B, which revealed a lack of activity against medically relevant Candida sp. and low cytotoxicity in vitro against human fibroblasts (MRC-5) and in vivo (zebrafish).

Complete Genome Sequence of Actinomadura Parvosata Subsp. Kistnae, A Rich Source of Novel Natural Product (Bio-)Chemistry.

The soil dwelling actinomycete strain Actinomadura parvosata subsp. kistnae is the producer of the antiviral antibiotics kistamicin A and B. Genome sequencing and bioinformatic analysis revealed the presence of the kistamycin biosynthetic gene cluster responsible for the formation of these non-ribosomal peptides as well as an impressive number of yet uncharacterized biosynthetic pathways. This includes polyketide, ribosomal and non-ribosomal peptide and a large number of terpenoid biosynthetic loci encoding yet unknown natural products. The genomic data of this strain is thus a treasure trove for genome mining for novel functional metabolites and new biocatalysts.

Tracing fatty acid metabolism by click chemistry.

Fatty acids are abundant constituents of all biological systems, and their metabolism is important for normal function at all levels of an organism. Aberrations in fatty acid metabolism are associated with pathological states and have become a focus of current research, particularly due to the interest in metabolic overload diseases. Here we present a click-chemistry-based method that allows tracing of fatty acid metabolism in virtually any biological system. It combines high sensitivity with excellent linearity and fast sample turnover. Since it is free of radioactivity, it can be combined with any other modern analysis technology and can be used in high-throughput applications. Using the new method, we provide for the first time an analysis of cellular fatty metabolism with high time resolution and a comprehensive comparison of utilization of a broad spectrum of fatty acids in hepatoma and adipose cell lines.