An Ultra High-Throughput, Whole-Animal Screen for Small Molecule Modulators of a Specific Genetic Pathway in <i>Caenorhabditis elegans</i>

<div><p>High-throughput screening (HTS) is a powerful approach to drug discovery, but many lead compounds are found to be unsuitable for use <i>in vivo</i> after initial screening. Screening in small animals like <i>C. elegans</i> can help avoid these problems, but this system has been limited to screens with low-throughput or no specific molecular target. We report the first <i>in vivo</i> 1536-well plate assay for a specific genetic pathway in <i>C. elegans</i>. Our assay measures induction of a gene regulated by SKN-1, a master regulator of detoxification genes. SKN-1 inhibitors will be used to study and potentially reverse multidrug resistance in parasitic nematodes. Screens of two small commercial libraries and the full Molecular Libraries Small Molecule Repository (MLSMR) of ∼364,000 compounds validate our platform for ultra HTS. Our platform overcomes current limitations of many whole-animal screens and can be widely adopted for other inducible genetic pathways in nematodes and humans.</p>