DNA旋转酶
化学
抗菌活性
谷胱甘肽
细胞毒性
抗菌剂
香豆素
组合化学
活性氧
生物化学
抗生素
细菌
体外
大肠杆菌
有机化学
酶
基因
生物
遗传学
作者
Xun-Cai Yang,Pengli Zhang,Kannekanti Vijaya Kumar,Shuo Li,Rong‐Xia Geng,Cheng‐He Zhou
标识
DOI:10.1016/j.ejmech.2022.114192
摘要
Unique coumarin conjugates with thiazolidinone as novel structural antibacterial modulators were exploited to combat the lethal multidrug-resistant bacterial infections. Bioactivity evaluation identified that indole-incorporated coumarin thiazolidinone conjugate 14a with low cytotoxicity to mammalian cells showed a broad antibacterial spectrum and exerted potent inhibition efficiencies to the tested germs at low concentrations (0.25-2 μg/mL). Moreover, the favorable performance of 14a in eradicating bacterial biofilm was beneficial to avert developing drug resistance. Mechanistic explorations revealed that molecule 14a was able to destroy cell membrane, leading to the leakage of intracellular materials and metabolism inhibition. The accumulation of excess reactive oxygen species (ROS) mediated by compound 14a could impede glutathione (GSH) activity and induce lipid peroxidation to suppress bacteria growth. Furthermore, compound 14a could not only intercalate into DNA base pair but also take part in non-covalent interaction with DNA gyrase B to hinder their biological function. Quantum chemical study indicated that molecule 14a had low HOMO-LUMO energy gap, which resulted in more stabilizing interactions and was conducive to displaying better antibacterial activity. ADMET analysis manifested that 14a possessed promising pharmacokinetic properties.
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