Novel Mandelic Acid Derivatives Containing 1,3,4-Oxadiazolyl Thioether for Enhancing Antibacterial Potential against Ralstonia solanacearum.

Bacterial wilt caused by Ralstonia solanacearum causes severe crop losses, yet effective agrochemicals remain scarce. Here, we designed a T3SS-targeting antivirulence agent that attenuates the pathogen virulence without inhibiting growth. Two series of mandelic acid and 2-amino-2-phenylacetic acid derivatives containing 1,3,4-oxadiazolyl thioethers were synthesized. High-throughput screening identified W40 (2-(4-chlorophenyl)-2-hydroxy-N-(5-((4-methylbenzyl)thio)-1,3,4-oxadiazol-2-yl)acetamide), which strongly inhibited hrpY expression without affecting bacterial growth. W40 exhibited significant protective activity against R. solanacearum infection in tomato and casuarina. qRT-PCR analysis showed that W40 suppressed T3SS-associated regulatory networks by downregulating key regulators, including prhG, phcA, prhA, and prhR. Phenotypic assays revealed that W40 impaired swimming motility but did not affect the extracellular cellulase activity, biofilm formation, or exopolysaccharide production. These findings highlight W40 as a promising lead compound for antivirulence therapy against bacterial wilt.