Abstract：
OBJECTIVE: This study aimed to develop an editable structural scaffold for improving drug development, including pharmacokinetics and pharmacodynamics of antibiotics by using synthetic compounds derived from a (hetero)aryl-quinoline hybrid scaffold.
RESULTS: In this study, 18 CF3-substituted (hetero)aryl-quinoline hybrid molecules were examined for their potential antibacterial activity against Staphylococcus aureus by determining minimal inhibitory concentrations. These 18 synthetic compounds represent modifications to key regions of the quinoline N-oxide scaffold, enabling us to conduct a structure-activity relationship analysis for antibacterial potency. Among the compounds, 3 m exhibited potency against with both methicillin resistant S. aureus strains, as well as other Gram-positive bacteria, including Enterococcus faecalis and Bacillus subtilis. We demonstrated that 3 m disrupted the bacterial proton motive force (PMF) through monitoring the PMF and conducting the molecular dynamics simulations. Furthermore, we show that this mechanism of action, disrupting PMF, is challenging for S. aureus to overcome. We also validated this PMF inhibition mechanism of 3 m in an Acinetobacter baumannii strain with weaken lipopolysaccharides. Additionally, in Gram-negative bacteria, we demonstrated that 3 m exhibited a synergistic effect with colistin that disrupts the outer membrane of Gram-negative bacteria.
CONCLUSIONS: Our approach to developing editable synthetic novel antibacterials underscores the utility of CF3-substituted (hetero)aryl-quinoline scaffold for designing compounds targeting the bacterial proton motive force, and for further drug development, including pharmacokinetics and pharmacodynamics.
RESULTS: In this study, 18 CF3-substituted (hetero)aryl-quinoline hybrid molecules were examined for their potential antibacterial activity against Staphylococcus aureus by determining minimal inhibitory concentrations. These 18 synthetic compounds represent modifications to key regions of the quinoline N-oxide scaffold, enabling us to conduct a structure-activity relationship analysis for antibacterial potency. Among the compounds, 3 m exhibited potency against with both methicillin resistant S. aureus strains, as well as other Gram-positive bacteria, including Enterococcus faecalis and Bacillus subtilis. We demonstrated that 3 m disrupted the bacterial proton motive force (PMF) through monitoring the PMF and conducting the molecular dynamics simulations. Furthermore, we show that this mechanism of action, disrupting PMF, is challenging for S. aureus to overcome. We also validated this PMF inhibition mechanism of 3 m in an Acinetobacter baumannii strain with weaken lipopolysaccharides. Additionally, in Gram-negative bacteria, we demonstrated that 3 m exhibited a synergistic effect with colistin that disrupts the outer membrane of Gram-negative bacteria.
CONCLUSIONS: Our approach to developing editable synthetic novel antibacterials underscores the utility of CF3-substituted (hetero)aryl-quinoline scaffold for designing compounds targeting the bacterial proton motive force, and for further drug development, including pharmacokinetics and pharmacodynamics.
摘要：
目的：本研究旨在开发一种可编辑的结构支架，用于通过使用衍生自（杂）芳基-喹啉混合支架的合成化合物来改善药物开发，包括抗生素的药代动力学和药效学。
结果：在这项研究中，通过测定最小抑制浓度,检查18个CF3-取代的(杂)芳基-喹啉杂合分子对金黄色葡萄球菌的潜在抗菌活性。这18种合成化合物代表了喹啉N-氧化物支架关键区域的修饰，使我们能够进行结构-活性关系（SAR）分析抗菌效力。在这些化合物中，3m表现出对两种耐甲氧西林金黄色葡萄球菌（MRSA）菌株的效力，以及其他革兰氏阳性菌，包括粪肠球菌和枯草芽孢杆菌。通过监测PMF并进行分子动力学模拟，我们证明了3m破坏了细菌质子动力（PMF）。此外，我们证明了这种作用机制，破坏PMF,对金黄色葡萄球菌来说是具有挑战性的。我们还在具有减弱的脂多糖（LPS）的鲍曼不动杆菌菌株中验证了3m的这种PMF抑制机制。此外,在革兰氏阴性细菌中，我们证明3m与粘菌素具有协同作用，破坏革兰氏阴性细菌的外膜。
结论：我们开发可编辑的合成新型抗菌药物的方法强调了CF3取代的（杂）芳基喹啉支架用于设计靶向细菌质子动力的化合物的实用性，为了进一步的药物开发，包括药代动力学和药效学。
结果：在这项研究中，通过测定最小抑制浓度,检查18个CF3-取代的(杂)芳基-喹啉杂合分子对金黄色葡萄球菌的潜在抗菌活性。这18种合成化合物代表了喹啉N-氧化物支架关键区域的修饰，使我们能够进行结构-活性关系（SAR）分析抗菌效力。在这些化合物中，3m表现出对两种耐甲氧西林金黄色葡萄球菌（MRSA）菌株的效力，以及其他革兰氏阳性菌，包括粪肠球菌和枯草芽孢杆菌。通过监测PMF并进行分子动力学模拟，我们证明了3m破坏了细菌质子动力（PMF）。此外，我们证明了这种作用机制，破坏PMF,对金黄色葡萄球菌来说是具有挑战性的。我们还在具有减弱的脂多糖（LPS）的鲍曼不动杆菌菌株中验证了3m的这种PMF抑制机制。此外,在革兰氏阴性细菌中，我们证明3m与粘菌素具有协同作用，破坏革兰氏阴性细菌的外膜。
结论：我们开发可编辑的合成新型抗菌药物的方法强调了CF3取代的（杂）芳基喹啉支架用于设计靶向细菌质子动力的化合物的实用性，为了进一步的药物开发，包括药代动力学和药效学。
