N1-Benzofused Modification of Fluoroquinolones Reduces Activity Against Gram-Negative Bacteria
N1-Benzofused Modification of Fluoroquinolones Reduces Activity Against Gram-Negative Bacteria
复制标题
DOI：
10.1021/acsomega.9b03910
复制
发表时间：
2020-06-02
期刊：
影响因子：
4.1
通讯作者：
Rahman, Khondaker Miraz
中科院分区：
文献类型：
--
作者：
Laws, Mark;Hind, Charlotte;Rahman, Khondaker Miraz
氟喹诺酮类抗生素具有完善的构效关系 (SAR) 和悠久的临床历史，但 N1 位富电子苯并稠合取代基的作用仍鲜有研究。由于该位置的基团是拓扑异构酶-DNA 结合复合物的一部分，并与 DNA 大沟形成疏水相互作用，因此推测富含电子的苯并稠合 N1 取代基可以增强这种相互作用。与环丙沙星和诺氟沙星相比，采用分子建模技术评估某些 N1 修饰的氟喹诺酮类药物与金黄色葡萄球菌和肺炎克雷伯菌 DNA 旋转酶靶标的结合。随后合成了七种 N1 修饰的氟喹诺酮类药物，并针对一组革兰氏阴性病原体进行测试，以确定最低抑制浓度 (MIC) 值。使用膜透化剂多粘菌素 B 九肽研究革兰氏阴性外膜渗透，并使用已知的外排泵抑制剂苯丙氨酸-精氨酸 β-萘酰胺评估通过抗性结节分裂家族外排转运蛋白的化合物外排。此外，代表性化合物 6e 的目标抑制活性是在无细胞环境中测定的。在整个 MIC 组中观察到 N1 取代基疏水性和活性之间的相关性，化合物活性随着疏水性的增加而降低。那些具有最高疏水性的化合物由于溶解度差而无活性，而具有中等疏水性的化合物由于外膜渗透受损和拓扑异构酶靶标的抑制减少而无活性，后者与模型预测相反。这项研究为氟喹诺酮类药物的 SAR 增加了新的信息，并表明氟喹诺酮类药物 N1 位上的大疏水取代基的效用有限。
The fluoroquinolone class of antibiotics has a well-established structure-activity relationship (SAR) and a long history in the clinic, but the effect of electron-rich benzofused substituents at the N1 position remains poorly explored. Because groups at this position are part of the topoisomerase-DNA binding complex and form a hydrophobic interaction with the major groove of DNA, it was hypothesized that an electron-rich benzofused N1 substituent could enhance this interaction. Molecular modeling techniques were employed to evaluate the binding of certain N1-modified fluoroquinolones to DNA gyrase targets from both Staphylococcus aureus and Klebsiella pneumoniae species compared with ciprofloxacin and norfloxacin. Seven N1-modified fluoroquinolones were subsequently synthesized and tested against a panel of Gram-negative pathogens to determine minimum inhibitory concentration (MIC) values. Gram-negative outer membrane penetration was investigated using the membrane permeabilizer polymyxin B nonapeptide and compound efflux via resistance-nodulation-division-family efflux transporters was evaluated using the known efflux pump inhibitor phenylalanine-arginine beta-naphthylamide. Additionally, the target inhibitory activity of representative compound 6e was determined in a cell-free environment. A correlation between N1 substituent hydrophobicity and activity was observed across the MIC panel, with compound activity decreasing with increased hydrophobicity. Those compounds with highest hydrophobicity were inactive because of poor solubility profiles whereas compounds with intermediate hydrophobicity were inactive because of impaired outer membrane penetration, and reduced inhibition of topoisomerase targets, the latter in contrast to modeling predictions. This study adds new information to the fluoroquinolone SAR and suggests limited utility of large hydrophobic substituents at the N1 position of fluoroquinolones.