Marine Actin-Associated Agents Cause Distinct In Vivo Neuromuscular, Epithelia, and Organogenesis Phenotype Profiles in Caenorhabditis elegans

Abstract Natural products that target microfilaments are indispensable cell biology tools and have been explored as anticancer agents but are impeded by poor selectivity. Research utility and therapeutic potential would benefit from an expanded menu of compounds with divergent pharmacokinetics, physiochemistry, and cell and organ activity. Marine sponges and cyanobacteria produce several actin-associated agents. Caenorhabditis elegans is a model for diverse whole-animal activities. Here, we compare in vivo activities of the well-characterized filament stabilizer jasplakinolide and destabilizer latrunculin A derived from sponges and more recently discovered hectochlorin, lyngbyabellin B, and lyngbyastatin 3 from cyanobacteria. We find that all these compounds inhibit larval development at low micromolar concentrations. Using behavioral, developmental, and reporter assays, we find a surprising variation in neuromuscular, cell biology, and organogenesis activities. In intestine cells, jasplakinolide frequently altered the lumen shape, latrunculin A frequently disrupted membrane polarization, lyngbyabellin B had mixed effects, and hectochlorin and lyngbyastatin 3 had weak effects. Lyngbyabellin B increased the vesicle density in epidermal cells. Latrunculin A disrupted gonad organogenesis and the positioning of integrin receptors. These results reveal divergent activity among marine actin-associated agents that could broaden therapeutic potential and demonstrate the use of C. elegans assays to help classify natural products and develop hypotheses for mechanisms.