Uncovering Lasonolide A Biosynthesis Using Genome-Resolved Metagenomics

Area of Science:

• Marine Natural Products Chemistry
• Microbial Genomics
• Bioorganic Chemistry

Background:

• Marine invertebrates, especially sponges, are prolific sources of novel bioactive compounds.
• Lasonolide A (LSA), a sponge-derived molecule, exhibits potent anticancer activity and a unique cytotoxicity profile.
• Limited supply of LSA from natural sources hinders its clinical development.

Purpose of the Study:

• To elucidate the biosynthetic pathway of lasonolide A (LSA).
• To identify the microbial producer of LSA within the marine sponge Forcepia sp.
• To investigate the genomic characteristics of the LSA-producing bacterium.

Main Methods:

• Genomic binning of the Forcepia sponge metagenome.
• Phylogenetic analysis based on 16S rRNA gene sequencing.
• Identification and analysis of the lasonolide A (las) biosynthetic gene cluster (BGC).

Main Results:

• A Gram-negative bacterium, tentatively named 'Candidatus Thermopylae lasonolidus' (phylum Verrucomicrobia), was identified as the putative LSA producer.
• This bacterium represents a new genus, with <89% 16S rRNA identity to its closest known relative.
• The las BGC was characterized as a trans-acyltransferase (AT) polyketide synthase (PKS) pathway, with three distinct copies found in the producer's genome, suggesting horizontal gene transfer and potential variations.

Conclusions:

• The study identifies a novel verrucomicrobial symbiont as the producer of the anticancer compound LSA.
• Genomic insights into the las BGC and producer genome provide a foundation for future cultivation and heterologous expression efforts.
• Overcoming the supply limitation of LSA through biotechnological approaches is crucial for its advancement as a potential anticancer therapeutic.