Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, Japan.
Molecules. 2024 Aug 10;29(16):3792. doi: 10.3390/molecules29163792.
() is a major bacterial infection in humans, leading to severe disease and causing death. The stagnation of antibiotic development in recent decades has made it difficult to combat drug-resistant infections. In this study, we performed an in silico structure-based drug screening (SBDS) targeting the MurE (saMurE) enzyme involved in cell wall synthesis of S. aureus. saMurE is an enzyme that is essential for the survival of but not present in humans. SBDS identified nine saMurE inhibitor candidates, Compounds -, from a structural library of 154,118 compounds. Among them, Compound showed strong antibacterial activity against () used as a model bacterium. Amino acid sequence homology between saMurE and MurE is 87.4%, suggesting that Compound has a similar inhibitory effect on . Compound showed an IC value of 301 nM for in the dose-dependent growth inhibition assay. Molecular dynamics simulation showed that Compound binds stably to both MurD and MurF, suggesting that it is a potential multi-pharmacological pharmacological inhibitor. The structural and bioactivity information of Compound , as well as its potential multiple-target activity, could contribute to developing new antimicrobial agents based on MurE inhibition.
金黄色葡萄球菌（）是一种严重的人类细菌性感染，可导致严重疾病并导致死亡。近几十年来抗生素研发的停滞，使得对抗耐药性感染变得更加困难。在这项研究中，我们针对参与金黄色葡萄球菌细胞壁合成的 MurE（saMurE）酶进行了基于结构的计算机药物筛选（SBDS）。saMurE 是一种对生存至关重要的酶，但在人类中不存在。SBDS 从 154,118 种化合物的结构文库中鉴定出了 9 种 saMurE 抑制剂候选物，分别为化合物 - 。其中，化合物 对作为模型菌的 （）表现出很强的抗菌活性。saMurE 和 MurE 的氨基酸序列同源性为 87.4%，表明化合物 对 可能具有相似的抑制作用。在剂量依赖性生长抑制试验中，化合物 对 的 IC 值为 301 nM。分子动力学模拟表明，化合物 与 MurD 和 MurF 都能稳定结合，表明它是一种潜在的多药理抑制剂。化合物 的结构和生物活性信息及其潜在的多靶点活性，可能有助于基于 MurE 抑制开发新的抗菌药物。
