Hong Ge, Li Weitian, Mao Lina, Wang Jiawen, Liu Tianjun
Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Front Chem. 2022 Aug 19;10:963442. doi: 10.3389/fchem.2022.963442. eCollection 2022.
A series of small-molecule fluoroquinolones were synthesized, characterized by HRMS and NMR spectroscopy, and screened for their antibacterial activity against MRSA, , and as model G/G pathogens. Compounds , , and were more potent than the reference drug balofloxacin against MRSA and (MIC values of 0.0195 and 0.039 μg/ml for , 0.039 and 0.078 μg/ml for each of and , respectively). Analysis of the time-dependent antibacterial effect of compound toward MRSA showed that in the early logarithmic growth phase, bactericidal effects occurred, while in the late logarithmic growth phase, bacterial inhibition occurred because of concentration effects and possibly the development of drug resistance. Compound exhibited low toxicity toward normal mammalian cell lines 3T3 and L-02 and tumor cell lines A549, H520, BEL-7402, and MCF-7. The compound was not hemolytic. Atomic force microscopy (AFM) revealed that compound could effectively destroy the membrane and wall of MRSA cells, resulting in the outflow of the cellular contents. Docking studies indicated the good binding profile of these compounds toward DNA gyrase and topoisomerase IV. ADMET's prediction showed that most of the synthesized compounds followed Lipinski's "rule of five" and possessed good drug-like properties. Our data suggested that compound exhibited potent anti-MRSA activity and is worthy of further investigation.
合成了一系列小分子氟喹诺酮类化合物，通过高分辨质谱（HRMS）和核磁共振光谱（NMR）进行表征，并筛选了它们对耐甲氧西林金黄色葡萄球菌（MRSA）、[此处原文缺失部分内容]以及作为典型革兰氏阳性/革兰氏阴性（G/G）病原体的[此处原文缺失部分内容]的抗菌活性。化合物[此处原文缺失部分内容]、[此处原文缺失部分内容]和[此处原文缺失部分内容]对MRSA和[此处原文缺失部分内容]的活性比参比药物巴洛沙星更强（[此处原文缺失部分内容]的MIC值分别为0.0195和0.039μg/ml，[此处原文缺失部分内容]和[此处原文缺失部分内容]各自的MIC值分别为0.039和0.078μg/ml）。对化合物[此处原文缺失部分内容]针对MRSA的时间依赖性抗菌作用分析表明，在对数生长早期阶段出现杀菌作用，而在对数生长后期阶段，由于浓度效应以及可能出现的耐药性发展导致细菌生长受到抑制。化合物[此处原文缺失部分内容]对正常哺乳动物细胞系3T3和L - 02以及肿瘤细胞系A549、H520、BEL - 7402和MCF - 7表现出低毒性。该化合物无溶血作用。原子力显微镜（AFM）显示化合物[此处原文缺失部分内容]可有效破坏MRSA细胞的细胞膜和细胞壁，导致细胞内容物外流。对接研究表明这些化合物与DNA回旋酶和拓扑异构酶IV具有良好的结合模式。ADMET预测显示，大多数合成化合物符合Lipinski的“五规则”并具有良好的类药性质。我们的数据表明化合物[此处原文缺失部分内容]表现出强效的抗MRSA活性，值得进一步研究。
