While sponges are valuable sources of bioactive natural products, a majority of these compounds are produced in small quantities by uncultured symbionts, hampering the study and clinical development of these unique compounds. Lasonolide A (LSA), isolated from marine sponge Forcepia sp., is a cytotoxic molecule active at nanomolar concentrations, which causes premature chromosome condensation, blebbing, cell contraction, and loss of cell adhesion, indicating a novel mechanism of action and making it a potential anticancer drug lead.

The genome sequence of the Forcepia sponge-derived bacterium Streptomyces sp. strain HB-N217 was determined, with approximately 8.25 Mbp and a G+C content of 72.1%. Thirty biosynthetic gene clusters that bear the capability to produce secondary metabolites were predicted. The results will aid marine natural product chemistry and sponge-microbe association studies.

Invertebrates, in particular sponges, have been a dominant source of new marine natural products. For example, lasonolide A (LSA) is a potential anti-cancer molecule isolated from the marine sponge Forcepia sp., with nanomolar growth inhibitory activity and a unique cytotoxicity profile against the National Cancer Institute 60 cell line screen. Here, we identified the putative biosynthetic pathway for LSA. Genomic binning of the Forcepia sponge metagenome revealed a gram-negative bacterium belonging to the phylum Verrucomicrobia as the candidate producer of LSA. Phylogenetic analysis showed this bacterium, herein named Candidatus Thermopylae lasonolidus, only has 88.78% 16S rRNA identity with the closest relative Pedosphaera parvula Ellin514, indicating it represents a new genus. The lasonolide A (las) biosynthetic gene cluster (BGC) was identified as a trans-AT polyketide synthase (PKS) pathway. When compared with its host genome, the las BGC exhibits a significantly different GC content and penta-nucleotide frequency, suggesting a potential horizontal acquisition of the gene cluster. Furthermore, three copies of the putative las pathway were identified in the candidate producer genome. Differences between the three las repeats were observed including the presence of three insertions, two single-nucleotide polymorphisms and the absence of a stand-alone acyl carrier protein in one of the repeats. Even though the Verrucomicrobial producer shows signs of genome-reduction, its genome size is still fairly large (about 5Mbp) and when compared to its closest free-living relative contains most of the primary metabolic pathways, suggesting that it is in the early stages of reduction.