Summary In the oceans, toxic secondary metabolites often protect otherwise poorly defended, soft-bodied invertebrates such as shell-less mollusks from predation. The origins of these metabolites are largely unknown, but many of them are thought to be made by symbiotic bacteria. In contrast, mollusks with thick shells and toxic venoms are thought to lack these secondary metabolites due to reduced defensive needs. Here, we show that heavily defended cone snails also occasionally contain abundant secondary metabolites, γ-pyrones known as nocapyrones, and that these pyrones are synthesized by symbiotic bacteria. This study shows that symbiotic bacteria can produce metabolites isolated from gastropod mollusks. The symbiotic bacteria, Nocardiopsis alba CR167, are closely related to potentially widespread actinomycetes that we propose to be casual symbionts of invertebrates on land and in the sea. The natural roles of nocapyrones are not known, but they are active in neurological assays at low micromolar levels, revealing that mollusks with external shells are an overlooked source of secondary metabolite diversity.

The bacterium Gordonia sp. 647W.R.1a.05 was cultivated from the venom duct of the cone snail, Conus circumcisus. The Gordonia sp. organic extract modulated the action potential of mouse dorsal root ganglion neurons. Assay-guided fractionation led to the identification of the new compound circumcin A (1) and 11 known analogs (2–12). Two of these compounds, kurasoin B (7) and soraphinol A (8), were active in a human norepinephrine transporter assay with Ki values of 2575 and 867 nM, respectively. No neuroactivity had previously been reported for compounds in this structural class. Gordonia species have been reproducibly isolated from four different cone snail species, indicating a consistent association between these organisms.