Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge <i>Theonella swinhoei</i>

TLDR

Marine sponges are believed to contain bacterial symbionts that produce many of their bioactive compounds, but this hypothesis has remained unproven because the suspected bacteria cannot be cultivated. We isolated genes from the complex metagenome of the sponge *Theonella swinhoei* that are closely related to the beetle symbiont’s polyketide biosynthetic genes and likely encode the antitumor polyketides onnamides and theopederins. These genes, which belong to a prokaryotic genome and account for most of the antitumor‑active polyketide structure, confirm the beetle symbiont hypothesis and point to biotechnological strategies for sustainably producing otherwise inaccessible marine drugs.

Abstract

Bacterial symbionts have long been suspected to be the true producers of many drug candidates isolated from marine invertebrates. Sponges, the most important marine source of biologically active natural products, have been frequently hypothesized to contain compounds of bacterial origin. This symbiont hypothesis, however, remained unproven because of a general inability to cultivate the suspected producers. However, we have recently identified an uncultured Pseudomonas sp. symbiont as the most likely producer of the defensive antitumor polyketide pederin in Paederus fuscipes beetles by cloning the putative biosynthesis genes. Here we report closely related genes isolated from the highly complex metagenome of the marine sponge Theonella swinhoei, which is the source of the onnamides and theopederins, a group of polyketides that structurally resemble pederin. Sequence features of the isolated genes clearly indicate that it belongs to a prokaryotic genome and should be responsible for the biosynthesis of almost the entire portion of the polyketide structure that is correlated with antitumor activity. Besides providing further proof for the role of the related beetle symbiont-derived genes, these findings raise intriguing ecological and evolutionary questions and have important general implications for the sustainable production of otherwise inaccessible marine drugs by using biotechnological strategies.