Project - What is GameXP about?

The majority of compounds used to treat disease come from a single group of organisms, the actinomycetes. This over-reliance on a single organism to produce the worlds drugs is a major problem for the development of compounds with alternative modes of action which can overcome constituitive or acquired drug resistance expressed by pathogenic organisms. To address this problem we will form an international multi-disciplinary group of experts to bioprospect for biologically active natural products. The central aim of GameXP is to develop a pipeline for the rapid discovery of novel drugs from non-actinomycete sources.

We will isolate novel bacterial strains of the proven but not well-explored drug producers Xenorhabdus and Photorhabdus spp. These entomopathogenic bacteria will be isolated from nematodes, characterized taxonomically, and analyzed for the production of novel compounds. This library of compounds will then be tested against a broad set of targets including bacteria, fungi, protozoans, nematodes, insects, and mammalian cell cultures. The most productive bacterial strains will then undergo whle genome sequencing and will be used to construct genomic libraries. These libraries will be used to generate recombinant clones in heterologous hosts, enabling fast and efficient biotechnological production of the bioactive compounds. To ensure efficient interactions and comparability of results, especially regarding the bioactivity data, training sessions will be organized with seminars and hands on experience for each of the groups at a central site.

Work in GameXP is subdivided into seven closely linked and interdependent Work Packages (WPs)



Figure 1. Pert diagram showing the project concept and work program flow. Connections regarding WP5 (Methodologies) and WP6 (Innovation-related activities) are shown as broken and dotted lines, respectively. WP (work package), WPL (Work package leader).

WP1 (Strain isolation/characterisation) is the basis for the whole project. A large and diverse strain collection of Xenorhabdus/Photorhabdus strains should be obtained from different locations. The work in WP1 will be carried out by experts in nematology and microbiology.

In WP2 (Chemistry/compound library) all Xenorhabdus/Photorhabdus strains are analyzed using analytical methods and new compounds are isolated in a preparative scale from large scale cultivations to build up a Xenorhabdus/Photorhabdus-specific compound library. This work will be carried out by expert natural product chemists and the goal is to generate a library of 50-100 Xenorhabdus/Photorhabdus-specific compounds.

These compounds will be analyzed in WP3 (Bioactivity testing) against multiple different targets (bacteria, fungi, protozoa, nematodes, insects, cell cultures) in parallel. In order to rapidly identify interesting strains, crude extracts should be tested using the same assays. This work will be carried out by biologists with expertise in these standard assays.

WP4 (Genome mining) will start after the first two strains showing the most promising biological activity have been identified within WP3. The aim of this WP is then to identify the biosynthesis gene clusters responsible for the production of the desired compounds which would allow their future exploitation and enables the heterologous production of these compounds in recombinant E. coli.

WP5 (Provision of harmonised set of methodologies) consists of two sessions. The initial session is required to ensure that all beneficiaries use the same or a comparable methodology regarding especially the bioactivity testing. The consolidation session should ensure that the methods used are comparable and involve methods used within WP4 (genome mining). This would ensure that e.g. RVA screens can be performed by different labs leading to reproducible results.

WP6 (Innovation-related activities) including management of all GAMEXP related intellectual property rights issues and coordination of dissemination activities, including the development of the overall dissemination strategy towards the scientific community and the broader public.

WP7 (Management) with overall responsibility for managing the different work package activities, monitoring timely submission of deliverables and the overall project progress to fulfil the tasks and objectives set out in the work programme, collecting data and preparing interim reports.