"Secondary metabolites (SMs) of bacterial origin play a pivotal role in modern therapy of various diseases. Whole-genome sequencing projects have revealed that all SM producing organisms have the capacity to produce many more compounds than reported from the respective strains. Despite their importance and their broad use in medicine, we hardly know anything about (i) the natural function of these important compounds, (ii) the underlying regulatory networks, and (iii) how to increase the number and yield of SMs produced by a single organism.
PROSECMET will address all these issues through the activities in four different work packages. As model organisms Photorhabdus and Xenorhabdus bacteria will be used that live in symbiosis with nematodes and together with them form an entomopathogenic complex.
WP1-Identification of SM targets. Derivatives of SMs will be synthesized allowing the identification of their molecular targets in bacteria, nematodes, insects and/or food competitors using methods of chemical biology.
WP2-Regulatory networks. External factors that activate SM production and if and how SMs act as internal signals in the producer will be identified (eg. by flow cytometry) with specific strains carrying SM biosynthesis gene promoters or promoter libraries fused to genes encoding different reporters (fluorescent proteins, resistance genes).
WP3-Increasing chemical diversity. Factors identified in WP2 will be applied to at least 100 different Photorhabdus and Xenorhabdus isolates in order to increase the number and the yield of SMs produced by them. Additionally, the genome of selected isolates will be sequenced in order to exchange the promoters responsible for SM biosynthesis leading to the production of additional compounds
WP4-Optimization of SM production. Using either regulatory elements identified in WP2 or artificially designed regulators, cell growth will be coupled to SM production, thus enabling the systematic construction of SM overproducers."
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