Development and Evaluation of 1-Hydroxypyridin-2(1 H )-one Derivatives as Antibacterial Agents against Pathogenic Pseudomonas aeruginosa

The global rise of multidrug-resistant bacteria has prompted an urgent need for new antibiotics, yet resistance continues to outpace discovery due to Gram-negative barriers, drug permeability issues, and limited industry investment. In this study, we synthesized a series of 1-hydroxypyridin-2-(1H)-one derivatives targeting Pseudomonas aeruginosa for analyses of antibacterial efficacy. Among these, LP07 displayed potent antibacterial activity across multiple strains, enhanced by subinhibitory colistin. Scanning electron microscopy suggested membrane-associated morphological changes, including surface collapse, shrinkage, and irregular cell shape, consistent with bactericidal effects. Safety profiling showed low CYP inhibition, minimal hERG liability, and no mammalian cytotoxicity. Taken together, LP07's whole-cell activity and observed membrane effects support its promise as a lead for further optimization.