A new type of benzopyrone-mediated quinolones (BMQs) was rationally designed and efficiently synthesized as novel potential antibacterial molecules to overcome the global increasingly serious drug resistance. Some synthesized BMQs effectively suppressed the growth of the tested strains, outperforming clinical drugs. Notably, ethylidene-derived BMQ 17a exhibited superior antibacterial potential with low MICs of 0.5–2 μg/mL to clinical drugs norfloxacin, it not only displayed rapid bactericidal performance and inhibited bacterial biofilm formation, but also showed low toxicity toward human red blood cells and normal MDA-kb2 cells. Mechanistic investigation demonstrated that BMQ 17a could effectually induce bacterial metabolic disorders and promote the enhancement of reactive oxygen species to disrupt the bacterial antioxidant defense system. It was found that the active molecule BMQ 17a could not only form supramolecular complex with lactate dehydrogenase, which disturbed the biological functions, but also effectively embed into calf thymus DNA, thus affecting the normal function of DNA and achieving cell death. This work would provide an insight into developing new molecules to reduce drug resistance and expand antibacterial spectrum.

合理设计并高效合成了一类新型苯并吡喃酮介导的喹诺酮类药物（BMQs）作为新型潜在抗菌分子，以克服全球日益严重的耐药性。一些合成的BMQs有效抑制了测试菌株的生长，其效果优于临床药物。值得注意的是，亚乙基衍生的 BMQ 17a比临床药物诺氟沙星表现出优越的抗菌潜力，其 MIC 为 0.5-2 μg/mL，不仅表现出快速杀菌性能并抑制细菌生物膜形成，而且对人红细胞和细菌表现出低毒性。正常 MDA-kb2 细胞。机理研究表明，BMQ 17a可以有效诱导细菌代谢紊乱，促进活性氧的增强，从而破坏细菌的抗氧化防御系统。研究发现，活性分子BMQ 17a不仅能与乳酸脱氢酶形成超分子复合物，扰乱其生物学功能，还能有效嵌入小牛胸腺DNA中，从而影响DNA的正常功能，实现细胞死亡。这项工作将为开发新分子以减少耐药性和扩大抗菌谱提供见解。