Bacteria of pharmaceutical interest in sea slugs for the first time

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The species of nudibranch Doriopsilla fulva was used in the study. Credits: Mári
The species of nudibranch Doriopsilla fulva was used in the study. Credits: Mária D¸unková.

An international research team in which the Institute for Integrative Systems Biology (I2SysBio), joint centre of the Higher Council for Scientific Research (CSIC) and the University of Valencia (UV) participate, has just published a study in the journal Microbiome which reveals the presence of beta-lactones, a group of little-studied substances with pharmaceutical potential generated by symbiotic bacteria that inhabit the skin of a species of nudibranch, a sea slug. It is the first time that a compound of pharmacological interest has been found in this group of molluscs, using an innovative technique that promises to broaden the knowledge of this type of substances of bacterial origin.

Nudibranchs comprise a group of more than 6,000 species of soft-bodied marine mollusks known as "sea slugs". They use secondary metabolites (natural substances) for their chemical defence, but the full diversity of these substances remains unexplored, so their potential therapeutic applications are unknown.

Scientists often search for genes encoding natural products of pharmacological interest in the genomes of uncultured microbes using computational tools, but there is no guarantee that the detected genes are functional. During her postdoctoral fellowship in the United States at Lawrence Berkeley National Laboratory, Mária D¸unková used a fluorescent probe developed at the University of California, San Diego to label bacteria that produce natural products.

D¸unková, a researcher at the University of Valencia at I2SysBio and the first signatory of the article in Microbiome, has explored the microbes that inhabit the nudibranch Doriopsilla fulva using fluorescence activated cell sorting (FACS) and microbial single cell genomics. With this technique, the bacteria that have absorbed the fluorescent probe are collected and the DNA present in single cells is amplified. This allows sufficient quantities to be obtained for whole genome sequencing of each separated cell, which allows the identification of new bacterial species without the need to grow them in the laboratory.

With this new technique she discovered the presence of the non-culturable bacterium Candidatus Doriopsillibacter californiensis, which belongs to an order of non-culturable bacteria. "This bacterium has genes for the production of beta-lactones, a little-explored molecular group with pharmaceutical potential that had not been detected before in nudibranchs", says the researcher. "Future research will reveal whether it is possible to use this compound to treat diseases such as cancer or infections caused by viruses or bacteria", reveals D¸unková.

According to the Slovakian researcher, who joined I2SysBio in 2021 to create its microbial single cell genomics research group, "this is the first study that documents a natural product from symbiotic microbes that inhabit the skin of nudibranchs".

Analyzing other species of nudibranchs from Spain

Her team analysed the microbial composition of several individuals of the nudibranch Doriopsilla fulva, found off the coast of San Francisco (California, USA), and confirmed that the bacterium Candidatus Doriopsillibacter californiensis is the most important member of the microbial community of your skin. Extracts from this nudibranch contained natural products consistent with the beta-lactone found in its symbiotic bacterium.

Since it is a non-culturable bacterium, the team at Lawrence Berkeley National Laboratory have used a new synthetic biology method called CRAGE (Chassis-independent Recombinase-Assisted Genome Engineering) developed in this laboratory, and are trying to recover the complete molecule. Meanwhile, the I2SysBio team analyses other nudibranch species in Spain (Galicia, the Basque Country, Andalusia and the Balearic Islands) and tries to discover more bacteria producing molecules of pharmaceutical interest.

Reference :

D¸unková, M., La Clair, J. J., Tyml, T. et al. ’Synthase-selected sorting approach identifies a beta-lactone synthase in a nudibranch symbiotic bacterium’. Microbiome 11, 130 (2023). DOI:­’023 -01560-8