A cationic amphiphilic drug synergizes with strobilurin fungicides to control fungal-borne plant diseases.

Fungal phytopathogens are responsible for major losses in agricultural yields annually. While the use of topical fungicides remains key to managing agricultural pathogens, the emergence of drug-resistant strains necessitates identifying additional treatment options. In this study, we performed an in vitro small molecule screen against the devastating cereal pathogen Fusarium graminearum, identifying CMLD009688 as a priority growth inhibitor. Chemical-genetic profiling and subsequent experiments with CMLD009688 revealed that this compound functions as a cationic amphiphilic drug (CAD) and perturbs vacuolar integrity in F. graminearum. CMLD009688 displayed synergy with strobilurin fungicides in limiting F. graminearum growth-likely through both compounds independently affecting vacuolar stability-and a combination treatment of CMLD009688 with the strobilurin pyraclostrobin strongly limited the virulence of both F. graminearum and Botrytis cinerea in distinct models of plant infection. Thus, our findings highlight that cationic amphiphilic molecules show immense promise in helping to protect crops from fungal diseases.