Combining B. thuringiensis crystal proteins with small molecule anthelmintics to combat parasitic nematode resistance

The project will pursue three major aims: Aim 1 will identify strong synergistic interactions using checkerboard design studies with six Cry proteins and three small molecule drugs (albendazole, ivermectin, emodepside) against three major GINs (Ancylostoma ceylanicum, Trichuris muris, Ascaris suum), quantifying synergy with the ZIP synergy model. Aim 2 will identify strong collateral sensitivity relationships by quantifying the sensitivity of drug-resistant Caenorhabditis elegans to Cry proteins and vice-versa, and quantifying the sensitivity of ABZ- and IVM-resistant Haemonchus contortus to Cry proteins and Cry protein-drug combinations using a larval development assay. The data from Aims 1 and 2 will be integrated to design and test optimal Cry protein-drug combinations for in vivo synergy against parasitic infections, conduct mechanistic studies using transcriptomics, and develop resistance management strategies via computer modeling.