Caenorhabditis elegans is a useful model for anthelmintic discovery

Abstract

Parasitic nematodes infect one quarter of the world's population and impact all humans through widespread infection of crops and livestock. Resistance to current anthelmintics has prompted the search for new drugs. Traditional screens that rely on parasitic worms are costly and labour intensive and target-based approaches have failed to yield novel anthelmintics. Here, we present our screen of 67,012 compounds to identify those that kill the non-parasitic nematode Caenorhabditis elegans. We then rescreen our hits in two parasitic nematode species and two vertebrate models (HEK293 cells and zebrafish), and identify 30 structurally distinct anthelmintic lead molecules. Genetic screens of 19 million C. elegans mutants reveal those nematicides for which the generation of resistance is and is not likely. We identify the target of one lead with nematode specificity and nanomolar potency as complex II of the electron transport chain. This work establishes C. elegans as an effective and cost-efficient model system for anthelmintic discovery.

El nematodo Caenorhabditis elegans como modelo para evaluar el potencial antihelmíntico de extractos de plantas

“…Burns et al (103) analizaron 67,012 compuestos para identificar aquéllos que afectaban la supervivencia de C. elegans; los compuestos seleccionados los vuelven a probar y seleccionan los que afectan a dos especies de nematodos parásitos y que no afectan a dos modelos vertebrados; finalmente identifican 30 moléculas con potencial antihelmíntico y después determinan de éstas, cuáles tienen la mayor probabilidad de generar resistencia en un periodo menor de tiempo. Estos trabajos, entre otros, han ayudado a establecer a C. elegans como un sistema modelo para el descubrimiento de antihelmínticos.…”

Is Caenorhabditis elegans the Magic Bullet for Anthelminthic Drug Discovery?

“…A recent study by Burns et al [6] published in Nature Communications now makes use of this powerful screening system. For the first time the authors demonstrate that C. elegans is a useful tool in high-throughput anthelminthic drug discovery.…”

“…Molecules killing C. elegans were 15 times more likely to kill C. onchophora and H. contortus. The authors concluded that C. elegans is an attractive prescreening model to identify anthelminthic leads, also in light of the speed and ease with which assays can be performed [6].…”

“…Burns et al have undertaken a range of logical follow-up studies to further characterize their leads [6]. Through counter-screening the hits against two vertebrate models and the use of structure-similarity networks, 30 unique classes of anthelminthic leads were identified.…”

“…Despite current challenges, the study by Burns et al [6] brings the field of anthelminthic drug discovery to the modern age, which is more than welcome. It will hopefully inspire research in anthelminthic research and development, stimulate discussions among researchers, and ultimately help to fill the depleted anthelminthic drug discovery pipeline.…”