Bacterial symbionts: prospects for the sustainable production of invertebrate-derived pharmaceuticals.

Invertebrate animals, such as sponges, tunicates and bryozoans, are among the most important sources of biomedically relevant natural products. However, as these animals generally contain only low quantities of the compounds, further pharmacological development is in most cases difficult. There is increasing evidence that many metabolites, in particular polyketides and nonribosomally synthesized peptides, are not produced by the animals themselves but by associated bacterial symbionts. This symbiont hypothesis currently attracts considerable interest, since it implicates that animal-independent production systems based on bacterial fermentation processes could be created. This review gives an overview about recent developments in the research on natural product symbiosis. Different techniques will be discussed that have been employed to pinpoint the actual producer. Since bacterial symbionts are highly fastidious and have been generally resistant to cultivation attempts, emphasis will be laid on culture-independent strategies, such as cell separation approaches and the cloning of biosynthetic genes. These strategies have provided insights into possible sources of several natural products, e.g. the bryostatins, pederin, the onnamides, swinholide A and theopalauamide. Finally, potential techniques for the generation of renewable supplies of symbiont-derived drug candidates will be discussed. Cultivation approaches and the heterologous expression of cloned biosynthesis genes from uncultured symbionts could in future provide access to several important marine drug candidates, including bryostatin 1, halichondrin or ET-743.