Discovery of Novel Antibacterial Agents against Plant Pathogens: Design, Synthesis, Antibacterial Activity, and Mechanism of Action of 1,2,4-Thiadiazole Derivatives Containing a Sulfone Moiety

Abstract

1,2,4-Thiadiazole derivatives containing a sulfone moiety were designed and synthesized via scaffold hopping to facilitate the discovery of novel antibacterial agents. Most of the compounds exhibited excellent activity against three plant pathogenic bacteria. The half-maximal effective concentrations (EC₅₀) of compound B7 for Xanthomonas oryzae pv oryzae (Xoo) and X. oryzae pv oryzicola (Xoc) concentrations were 0.4 and 1.0 mg/L, respectively. In addition, the EC₅₀ values of compounds B1 and B24 for Xoo, Xoc, and Pseudomonas syringae pv actinidiae (Psa) were less than 5 mg/L and significantly better than those of the positive control agents thiodiazole copper (121.8, 119.5, and 142.0 mg/L, respectively) and bismerthiazol (73.3, 65.6, and 128.8 mg/L, respectively). Compound B7 exhibited protective and curative activities of 48.1 and 46.7%, respectively, against bacterial leaf blight, which were higher than those of bismerthiazol (35.5 and 36.9%, respectively) and thiodiazole copper (39.3 and 39.5%, respectively). Additionally, compound B7 exerted an effect on the virulence factors of Xoo (production of exopolysaccharides and extracellular enzymes, biofilm formation, and motility), membrane permeability, cell surface morphology, and intracellular content of reactive oxygen species. Transcriptome analysis showed that compound B7 improved the resistance of rice plants to external stress by influencing the metabolic process, biological regulation, catalytic activity of enzymes, and plant-pathogen interaction. Compound B7 can therefore be considered as a potential candidate antibacterial agent and warrants an in-depth investigation in the future.

Keywords: 1,2,4-thiadiazole; antibacterial activity; mechanism; scaffold hopping; virulence factor.