Design, Synthesis, and Bioactivity Evaluation of Novel 1-Methyl-2-phenylpyridin-1-ium Derivatives as Broad-Spectrum FtsZ Inhibitors.

To address the threat of bacterial infections in animal husbandry, a novel class of 1-methyl-2-phenylpyridin-1-ium derivatives has been designed and synthesized as broad-spectrum antibacterial agents to counteract increasing multidrug resistance. Biological assays revealed that compounds 4n, 16b, 16c, and 16e exhibited superior inhibition of S. aureus ATCC25923 (MICs = 0.0625-0.5 μg/mL) and A. baumannii ATCC19606 (MICs = 1-4 μg/mL) compared to linezolid and vancomycin. Mechanistic studies revealed that 16e promoted FtsZ polymerization, disrupted proton gradients, and increased the bacterial membrane permeability. Hemolytic toxicity assessments confirmed the favorable biological safety profile of 16e. In vivo studies using a mouse model of bacteremia demonstrated the superior antibacterial efficacy of 16e to linezolid. Molecular dynamics simulations showed that 16e could maintain the FtsZ protein in the T state, which was conducive to FtsZ polymerization. These results provide new therapeutic strategies to deal with the emerging bacterial resistance in animal husbandry.