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 <b>4n</b>, <b>16b</b>, <b>16c</b>, and <b>16e</b> exhibited superior inhibition of <i>S. aureus</i> ATCC25923 (MICs = 0.0625-0.5 μg/mL) and <i>A. baumannii</i> ATCC19606 (MICs = 1-4 μg/mL) compared to linezolid and vancomycin. Mechanistic studies revealed that <b>16e</b> promoted FtsZ polymerization, disrupted proton gradients, and increased the bacterial membrane permeability. Hemolytic toxicity assessments confirmed the favorable biological safety profile of <b>16e</b>. <i>In vivo</i> studies using a mouse model of bacteremia demonstrated the superior antibacterial efficacy of <b>16e</b> to linezolid. Molecular dynamics simulations showed that <b>16e</b> 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.