Zheng Wende, Tu Borong, Zhang Zhen, Li Jinxuan, Yan Zhenping, Su Kaize, Deng Duanyu, Sun Ying, Wang Xu, Zhang Bingjie, Zhang Kun, Wong Wing-Leung, Wu Panpan, Hong Weiqian David, Ang Song
School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, China.
International Healthcare Innovation Institute, Jiangmen, China.
Front Chem. 2023 Jan 6;10:1094841. doi: 10.3389/fchem.2022.1094841. eCollection 2022.
Fusidic acid () has been widely applied in the clinical prevention and treatment of bacterial infections. Nonetheless, its clinical application has been limited due to its narrow antimicrobial spectrum and some side effects. Therefore, it is necessary to explore the structure-activity relationships of derivatives as antibacterial agents to develop novel ones possessing a broad antimicrobial spectrum. First, a pharmacophore model was established on the nineteen derivatives with remarkable antibacterial activities reported in previous studies. The common structural characteristics of the pharmacophore emerging from the derivatives were determined as those of six hydrophobic centers, two atom centers of the hydrogen bond acceptor, and a negative electron center around the C-21 field. Then, seven derivatives have been designed according to the reported structure-activity relationships and the pharmacophore characteristics. The designed derivatives were mapped on the pharmacophore model, and the Qfit values of all derivatives were over 50 and possessed the highest value of 82.66. The molecular docking studies of the partial target compounds were conducted with the elongation factor G (EF-G) of . Furthermore, the designed derivatives have been prepared and their antibacterial activities were evaluated by the inhibition zone test and the minimum inhibitory concentration (MIC) test. The derivative with a chlorine group as the substituent group at C-25 of displayed the best antibacterial property with an MIC of 3.125 µM. Subsequently, 3D-QSAR was carried on all the derivatives by using the CoMSIA mode of SYBYL-X 2.0. Hence, a computer-aided drug design model was developed for , which can be further used to optimize derivatives as highly potent antibacterial agents.
夫西地酸（）已广泛应用于细菌感染的临床防治。然而，由于其抗菌谱窄和一些副作用，其临床应用受到限制。因此，有必要探索夫西地酸衍生物作为抗菌剂的构效关系，以开发具有广谱抗菌活性的新型衍生物。首先，基于先前研究报道的19种具有显著抗菌活性的夫西地酸衍生物建立了药效团模型。从这些衍生物中得出的药效团的共同结构特征被确定为六个疏水中心、两个氢键受体原子中心以及C-21区域周围的一个负电子中心。然后，根据报道的构效关系和药效团特征设计了七种夫西地酸衍生物。将设计的夫西地酸衍生物映射到药效团模型上，所有衍生物的Qfit值均超过50，其中最高值为82.66。对部分目标化合物与金黄色葡萄球菌的延伸因子G（EF-G）进行了分子对接研究。此外，制备了设计的夫西地酸衍生物，并通过抑菌圈试验和最低抑菌浓度（MIC）试验评估了它们的抗菌活性。在夫西地酸的C-25位带有氯原子作为取代基的衍生物表现出最佳的抗菌性能，MIC为3.125 μM。随后，使用SYBYL-X 2.0的CoMSIA模式对所有衍生物进行了3D-QSAR研究。因此，建立了夫西地酸的计算机辅助药物设计模型，该模型可进一步用于优化夫西地酸衍生物，以获得高效抗菌剂。
