Metagenomic Analysis of the Sponge <i>Discodermia</i> Reveals the Production of the Cyanobacterial Natural Product Kasumigamide by ‘Entotheonella’

<div><p>Sponge metagenomes are a useful platform to mine cryptic biosynthetic gene clusters responsible for production of natural products involved in the sponge-microbe association. Since numerous sponge-derived bioactive metabolites are biosynthesized by the symbiotic bacteria, this strategy may concurrently reveal sponge-symbiont produced compounds. Accordingly, a metagenomic analysis of the Japanese marine sponge <i>Discodermia calyx</i> has resulted in the identification of a hybrid type I polyketide synthase-nonribosomal peptide synthetase gene (<i>kas</i>). Bioinformatic analysis of the gene product suggested its involvement in the biosynthesis of kasumigamide, a tetrapeptide originally isolated from freshwater free-living cyanobacterium <i>Microcystis aeruginosa</i> NIES-87. Subsequent investigation of the sponge metabolic profile revealed the presence of kasumigamide in the sponge extract. The kasumigamide producing bacterium was identified as an ‘Entotheonella’ sp. Moreover, an <i>in silico</i> analysis of <i>kas</i> gene homologs uncovered the presence of <i>kas</i> family genes in two additional bacteria from different phyla. The production of kasumigamide by distantly related multiple bacterial strains implicates horizontal gene transfer and raises the potential for a wider distribution across other bacterial groups.</p>