OMICs based analysis of cytochalasans in fungal-bacteria-insect interactions

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The main objective of this proposal is to study the structural diversity and functions of cytochalasans in fungus-bacteria-insect interactions using an OMICs-based approach (metabolomics, genomics, transcriptomics). The proposal is based on three specific workinghypotheses: 1) The production of cytochalasans per se and synergizing secondary metabolites in fungi is triggered by bacterial signals and insect-derived components and enables the pathogen to thrive on insects; 2) functionalized cytochalasans can be applied to identify non-actin like cellular/bacterial targets; 3) natural promiscuity of cytochalasan biosynthesis can be exploited to create a substrate library for biological testing. These three hypotheses will be investigated in four complementary and defined work packages, which aim for the detailed metabolomic and transcriptomic analysis of fungus-bacteria and fungus-insect interactions assays (WP1), thedetermination of synergistic activities of natural cytochalasans combinations (WP2), the application of bifunctional cytochalasans to identify bacterial targets (Wp3), and the expansion of the cytochalasan library by exploiting the natural promiscuity of cytochalasan-encoding biosynthetic pathways (WP4). Within the funding period, this project aims to establish a more general and standardized experimental set-up for studying cross-kingdom interactions on a metabolomic and transcriptomic level, which will serve in long-term as tool to analyse important fungus-bacteria interactions in a broader context. Results of this project will provide detailed insights into the mechanisms by which entomopathogenic or parasitic fungi apply cytochalasans to kill bacterial defensive symbionts and the insect host. Our overall findings will help to rationally develop novel antimicrobial cytochalasans, identify their bacterial targets and to provide valuable insights into the phylogenetic history and regulation of cytochalasan-related BGCs.