Design, synthesis and biological evaluation of amphiphilic benzopyran derivatives as potent antibacterial agents against multidrug-resistant bacteria

被引:2
|
作者
Liu, Fangquan [1 ]
Yang, Siyu [1 ]
Zhang, Lei [1 ]
Zhang, Meiyue [1 ]
Bi, Ying [1 ]
Wang, Shuo [1 ]
Wang, Xuekun [1 ]
Wang, Yinhu [1 ]
机构
[1] Liaocheng Univ, Sch Pharmaceut Sci & Food Engn, State Key Lab Macromol Drugs & Large Scale Mfg, Liaocheng 252059, Peoples R China
基金
中国国家自然科学基金;
关键词
Bacterial resistance; AMPs; Membrane-targeting; Benzopyran derivatives; MEMBRANE-ACTIVE ANTIMICROBIALS; XANTHONE DERIVATIVES; ANTIBIOTICS; PEPTIDES; MIMICS; MECHANISM;
D O I
10.1016/j.ejmech.2024.116784
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Antimicrobial resistance has emerged as a significant threat to global public health. To develop novel, high efficiency antibacterial alternatives to combat multidrug-resistant bacteria, A total of thirty-two novel amphiphilic benzopyran derivatives by mimicking the structure and function of antimicrobial peptides were designed and synthesized. Among them, the most promising compounds 4h and 17e displayed excellent antibacterial activity against Gram-positive bacteria (MICs = 1-4 mu g/mL) with weak hemolytic activity and good membrane selectivity. Additionally, compounds 4h and 17e had rapid bactericidal properties, low resistance frequency, good plasma stability, and strong capabilities of inhibiting and eliminating bacterial biofilms. Mechanistic studies revealed that compounds 4h and 17e could effectively disrupt the integrity of bacterial cell membranes, and accompanied by an increase in intracellular reactive oxygen species and the leakage of proteins and DNA, ultimately leading to bacterial death. Notably, compound 4h exhibited comparable in vivo antibacterial potency in a mouse septicemia model infected by Staphylococcus aureus ATCC43300, as compared to vancomycin. These findings indicated that 4h might be a promising antibacterial candidate to combat antimicrobial resistance.
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页数:17
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