Dai Jie, Li Qianyue, Li Ziyi, Zang Zhonglin, Luo Yan, Zhou Chenghe
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.
College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, China.
Molecules. 2025 Jan 9;30(2):243. doi: 10.3390/molecules30020243.
The overprescription of antibiotics in medicine and agriculture has accelerated the development and spread of antibiotic resistance in bacteria, which severely limits the arsenal available to clinicians for treating bacterial infections. This work discovered a new class of heteroarylcyanovinyl quinazolones and quinazolone pyridiniums to surmount the increasingly severe bacterial resistance. Bioactive assays manifested that the highly active compound exhibited strong inhibition against MRSA and with extremely low MICs of 0.5 μg/mL, being eightfold more active than that of norfloxacin (MICs = 4 μg/mL). The highly active with rapid bactericidal properties displayed imperceptible resistance development trends, negligible hemolytic toxicity, and effective biofilm inhibitory effects. Preliminary explorations on antibacterial mechanisms revealed that compound could cause membrane damage, embed in intracellular DNA to hinder bacterial DNA replication, and induce metabolic dysfunction. Surprisingly, active was found to trigger the conformational change in PBP2a of MRSA to open the active site, which might account for its high inhibition against MRSA. In addition, the little effect of molecule on the production of reactive oxygen species indicated that bacterial death was not caused by oxidative stress. The above comprehensive analyses highlighted the large potential of quinazolone pyridiniums as multitargeting broad-spectrum antibacterial agents.
医学和农业中抗生素的过度处方加速了细菌对抗生素耐药性的发展和传播，这严重限制了临床医生治疗细菌感染可用的药物库。这项研究发现了一类新型的杂芳基氰基乙烯基喹唑啉和喹唑啉吡啶鎓，以克服日益严重的细菌耐药性。生物活性测定表明，该高活性化合物对耐甲氧西林金黄色葡萄球菌（MRSA）表现出强烈抑制作用，其最低抑菌浓度（MIC）极低，为0.5μg/mL，活性比诺氟沙星（MIC = 4μg/mL）高八倍。具有快速杀菌特性的高活性化合物显示出难以察觉的耐药性发展趋势，溶血毒性可忽略不计，并具有有效的生物膜抑制作用。对抗菌机制的初步探索表明，该化合物可导致膜损伤，嵌入细胞内DNA以阻碍细菌DNA复制，并诱导代谢功能障碍。令人惊讶的是，发现活性化合物会引发MRSA的PBP2a构象变化以打开活性位点，这可能是其对MRSA具有高抑制作用的原因。此外，该分子对活性氧产生的影响较小，表明细菌死亡不是由氧化应激引起的。上述综合分析突出了喹唑啉吡啶鎓作为多靶点广谱抗菌剂的巨大潜力。
