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High-throughput screening (HTS) is a powerful approach to drug discovery, but many lead compounds are found to be unsuitable for use  in vivo  after initial screening. Screening in small animals like  C. elegans  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  in vivo  1536-well plate assay for a specific genetic pathway in  C. elegans . 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.

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