Biosynthesis of the selective Gq protein inhibitor FR900359 in Chromobacterium vaccinii as basis for compound supply and structural modifications

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The depsipeptide FR900359 (FR) is a selective inhibitor of Galphaq proteins and thus extremely useful as a pharmacological tool. This natural product is present in the higher plant Ardisia crenata, which is known to harbor symbiotic bacteria of the genus Burkholderia. To date, we sequenced the genes for a putative nonribosomal peptide synthetase from the endophytic Burkholderia. Within the project the biosynthesis of FR will be elucidated on the genetic and biochemical level. This shall serve as a basis for the heterologous expression and genetic engineering of FR derivatives. The sequence of the biosynthetic gene cluster for FR production will also be employed for mining publicly available bacterial genomes for bacterial strains, being able to produce FR or related compounds. Structural variants of FR will also be obtained by direct semi-synthetic modification of FR, and additionally by addressing the isolation of minor depsipeptide-metabolites from A. crenata. Further depsipeptides shall be obtained from other Ardisia species known to have bacterial symbionts. All FR derivatives will be assessed in comparison to FR for their bioactivity and will give a deep insight into structure-activity relationships.