Plant parasitic nematodes (PPNs) cause about 12% yield loss in agriculture annually, with root-knot nematodes (RKNs) being among the most harmful nematodes. They invade the root and form nematode feeding sites (NFS) in the vascular cylinder by inducing a series of morphological, molecular and biochemical changes in plant root cells, causing severe biotic stress in plants. Moreover, NFS are the sole food source for growth and reproduction of these nematodes and form an important target for PPN control. The aim of this project is to identify compounds that can specifically protect plants from nematode infections by inducing resistance, without affecting normal developmental processes. For this purpose, we will develop and perform a chemical genetics screen in conditions representative for early stages of nematode infection, using a promoter-GUS-GFP reporter line in Arabidopsis thaliana. The marker gene, to be selected based on single-cell RNA sequencing data, will be specifically up- or downregulated upon RKN infection within the NFS, in both Arabidopsis and rice. The selected compounds from the screen will subsequently be subjected to a structure-activity relationship analysis to generate more potent compounds. Finally, these optimized compounds will be validated in pot experiments with different nematode-crop interactions. We expect to find a small set of validated compounds that affect nematode infection in some economically relevant crop species, especially in rice.