Structure and biosynthesis of unusual polyamine and polyagmatine natural products

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Entomopathogenic bacteria of the genera Photorhabdus and Xenorhabdus have been proven to be a rich source for novel natural products. However, their structure and biosynthesis is often still unknown. Therefore the biosynthesis of two structurally very unusual natural product classes will be investigated in detail in this project:1. Polyamine natural products with similarity to zeamine.Zeamine is only one of three known members of a highly unusual class of natural products with broad antimicrobial activity. It is a linear long-chain amine (>30 carbon atoms in length) with additional amine substituents. Biochemically, this unusual structure in likely to be derived from a pathways similar to the biosynthesis of polyunsaturated fatty acids but it represents a new subtype of this biosynthesis. From Xenorhabdus budapestensis we have identified and elucidated the structure of another member of this class of compounds, which was named xenoGUFamine. In this compound the polyamine moiety is attached to a nonribosomally made cyclic peptide with the cyclisation mechanism being unknown. XenoGUFamine also shows broad antimicrobial activity but is also highly cytotoxic. Preliminary work revealed that several Xenorhabdus but also Photorhabdus strains that live in symbiosis with nematodes and are entomopathogenic are able to produce similar compounds. Subsequent analysis of the genome sequences of several of these bacteria also led to the identification of the respective biosynthesis gene clusters.2. Polyagmatine natural products with similarity to nemaucin.The only known members of this second unusual class of natural products are phleomycin G, nemaucin and cabanillasin. Nemaucin and cabanillasin have been isolated from Xenorhabdus cabanillasii and were described in patents by a French company because they also show a broad and potent antimicrobial activity similar to the polyamines. Nemaucin has a peptide moiety very similar to that of xenoGUFamine but carries a polyagmatine instead of the polyamine moiety. Currently nothing in known about the biosynthesis of this highly unusual polyagmatine moiety.In this project additional members of these very unusual classes of natural products, which obviously is very common in entomopathogenic bacteria, will be identified and their structures will be elucidated. The respective biosynthesis gene clusters will be identified and analysed and selected enzymes will be characterized in vitro. Additionally, the biological activity of these compounds will be investigated in more detail and first experiments regarding the mode of action of these compounds will be performed.