C. elegans has long been a model system for parasitic worms, or helminths. Anthelmintic treatments affect C. elegans and helminths similarly, and the mechanisms of action for commercially available anthelmintics were elucidated in C. elegans. Previously, we reported the identification of CL-5, a chemical with anthelmintic activity, from our library of natural product derivatives. CL-5 affects worm motility and survival in two microscale, liquid-based assays. When added to NGM plates, CL-5 shortens lifespan at low concentrations and causes death within minutes or hours at higher concentrations. CL-5 is effective against mutant strains that are resistant to the major anthelmintics on the market, including ivermectin, benomyl, and levamisole, suggesting a novel mode of action. CL-5 is structurally related to resveratrol, and high levels of resveratrol attenuate the motility and killing effects of CL-5. Resveratrol is reported to lower oxidative stress in C. elegans, thereby increasing longevity. Treatment with CL-5 leads to nuclear localization of DAF-16::GFP and increased expression of its target gene
sod-3, both of which are indicators of oxidative stress. Using the Amplex Red assay, elevated levels of hydrogen peroxide were detected in wildtype animals treated with CL-5 compared to controls.
gas-1 mutants, which are defective in a subunit of Complex I in the mitochondrial electron transport chain (ETC) and exhibit increased ROS, are hypersensitive to CL-5. Likewise,
clk-1 mutants that prevent biosynthesis of the electron carrier ubiquinone show increased sensitivity to CL-5. When wildtype animals were exposed to both CL-5 and ubiquinone in our liquid assay, rates of paralysis decreased compared to worms treated with only CL-5. Furthermore, ubiquinone supplementation in solid plates containing CL-5 dramatically reduced the percentage of animals that die. Additional experiments are underway to explore whether CL-5 elicits its effects by perturbing normal mitochondrial function.