Ren Yixin, Dong Wenting, Li Yan, Cao Weiting, Xiao Zengshuo, Zhou Ying, Teng Yun, You Xuefu, Yang Xinyi, Huang Huoqiang, Wang Hao
Key Laboratory of Mass Spectrometry Imaging and Metabolomics (Minzu University of China), National Ethnic Affairs Commission, Beijing 100081, China.
Institute of National Security, Minzu University of China, Beijing 100081, China.
Molecules. 2024 Apr 17;29(8):1827. doi: 10.3390/molecules29081827.
Antibiotic resistance in Gram-negative bacteria remains one of the most pressing challenges to global public health. Blocking the transportation of lipopolysaccharides (LPS), a crucial component of the outer membrane of Gram-negative bacteria, is considered a promising strategy for drug discovery. In the transportation process of LPS, two components of the LPS transport (Lpt) complex, LptA and LptC, are responsible for shuttling LPS across the periplasm to the outer membrane, highlighting their potential as targets for antibacterial drug development. In the current study, a protein-protein interaction (PPI) model of LptA and LptC was constructed, and a molecular screening strategy was employed to search a protein-protein interaction compound library. The screening results indicated that compound 18593 exhibits favorable binding free energy with LptA and LptC. In comparison with the molecular dynamics (MD) simulations on currently known inhibitors, compound 18593 shows more stable target binding ability at the same level. The current study suggests that compound 18593 may exhibit an inhibitory effect on the LPS transport process, making it a promising hit compound for further research.
革兰氏阴性菌的抗生素耐药性仍然是全球公共卫生面临的最紧迫挑战之一。阻断脂多糖（LPS）的运输，脂多糖是革兰氏阴性菌外膜的关键组成部分，被认为是一种有前景的药物发现策略。在LPS的运输过程中，LPS运输（Lpt）复合物的两个组分LptA和LptC负责将LPS穿梭穿过周质到达外膜，这突出了它们作为抗菌药物开发靶点的潜力。在当前研究中，构建了LptA和LptC的蛋白质-蛋白质相互作用（PPI）模型，并采用分子筛选策略搜索蛋白质-蛋白质相互作用化合物库。筛选结果表明化合物18593与LptA和LptC表现出良好的结合自由能。与目前已知抑制剂的分子动力学（MD）模拟相比，化合物18593在相同水平上显示出更稳定的靶点结合能力。当前研究表明化合物18593可能对LPS运输过程具有抑制作用，使其成为进一步研究的有前景的命中化合物。
