Browsing by Author "Andsten, Rose-Marie"

Bacteria are a great source of natural products with complex chemical structures and diverse biological activities. Many have therapeutic properties and half of drugs in clinical use today are derived directly or indirectly from natural products. The pharmaceutical industry stopped investing in drug development from natural resources, due to perceived limitations in chemical space, and difficulties in rediscovery of known compounds and in obtaining sufficient quantities of natural products for clinical trials. There is now renewed interest in natural products as drug leads driven by technological advances in genome sequencing and analytical chemistry. Cyanobacteria produce a variety of natural products with therapeutic potential. Muscoride A is an unusual peptide alkaloid produced by a terrestrial freshwater cyanobacterium with reported antimicrobial activity. The aim of this study was to characterize the biosynthetic origin and biological activity of muscoride A. I identified the 12.7 kb muscoride (mus) biosynthetic gene cluster from a draft genome of Nostoc sp. PCC 7906 using bioinformatics analysis. The mus biosynthetic gene cluster encoded enzymes for the heterocyclization, oxidation and prenylation of a precursor protein. Comparative genomics identified a mus biosynthetic gene cluster in the unpublished draft genome of Nostoc sp. UHCC sp. 0398 encoding a novel muscoride. This novel muscoride, muscoride B, was detected from Nostoc sp. UHCC 0398 based on this analysis. Muscoride B was purified using solid phase extraction and high-performance liquid chromatography and the chemical structure was verified by combining nuclear magnetic resonance and mass spectrometry data. Furthermore, the function and evolutionary history of the muscoride prenyltransferases were studied. A significant finding was that the biosynthetic pathway encodes two regiospecific prenyltransferases, catalyzing the C- and N-terminal prenylation of muscoride. An antimicrobial activity screening showed that muscoride B had antimicrobial activity against Bacillus cereus. Here I report the discovery of the muscoride biosynthetic pathway and the discovery of a novel antimicrobial peptide from cyanobacteria through genome mining. The results show that the variant is a novel muscoride, a linear bis-prenylated polyoxazole pentapeptide with antimicrobial activity.