C. Elegans as a screening platform for drug discovery

HERNANDO, G.; TURANI, O.; RODRIGUEZ ARAUJO, N.; BOUZAT, C.

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAB AAFE AACYTAl 2023; 2023

The free-living nematode Caenorhabditis elegans is awidely utilized model organism in various fields of modernbiology. Its advantages, such as its easy manipulability,low maintenance cost, short reproductive cycle of approximatelythree days, large brood size of 300 progeniesper hermaphrodite worm, and transparent body, make itthe ideal choice for drug discovery screenings. Notably,C. elegans possesses the largest known Cys-loop receptorfamily, along with unique receptors absent in vertebrates,which present attractive targets for anthelminticdrugs. Additionally, this nematode has shown promisein the search for new therapeutic compounds, includingEssential Oils (EOs). EOs have found extensive applicationsin human and veterinary health, with their activeagents being isolated and incorporated into numerouspharmaceutical preparations. Our hypothesis states thatEOs derived from aromatic plants commonly used in aromatherapyor as food additives contain compounds withanthelmintic activity. To test this hypothesis, we utilize C.elegans as a model organism for parasitic nematodes.We have developed behavioral and molecular assaysusing both wild-type and mutant worms lacking Cys-loopreceptors involved in locomotion. These assays aim toidentify the primary compounds within EOs that mediateanthelmintic activities and their respective pharmacologicaltargets. Furthermore, we explore the combination ofcurrent anthelmintics with active compounds from EOsas a strategy to mitigate drug resistance.Our objective is to provide a robust platform for the discoveryof novel antiparasitic compounds. Through ourresearch, we have identified six distinct EOs that inhibitC. elegans locomotion and egg hatching, each exhibitingvarying levels of potency, thereby indicating their anthelminticcapacity. Moreover, we have successfully identifiedthe key bioactive compounds and receptor targetsassociated with these EOs using single-channel andwhole-cell recordings from cultured C. elegans musclecells. These findings have allowed us to elucidate themolecular mechanisms behind the modulation of C. elegansnicotinic and GABA receptors by these compounds.In conclusion, our results highlight EOs as valuablesources of natural compounds with promising polypharmacologicalprofiles for anthelmintic therapies. We havedeciphered the molecular basis of their actions and providedinsights into the efficacy of drug combinations asstrategies to combat drug resistance in nematodes.