Wang Jianfeng, Zhou Xuan, Liu Shui, Li Gen, Zhang Bing, Deng Xuming, Niu Xiaodi
Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Sci Rep. 2015 Mar 9;5:8864. doi: 10.1038/srep08864.
Increasing bacterial resistance to available antibiotics makes the discovery of novel efficacious antibacterial agents a priority. A previous report showed that listeriolysin O (LLO) is a critical virulence factor and suggested that it is a target for developing anti-virulence drugs against Listeria monocytogenes infections. In this study, we report the discovery of LLO natural compound inhibitors with differential activity by using hemolysis assay. The mechanism of action of the inhibitors was consistent with that of fisetin, a natural flavonoid without antimicrobial activity, which we showed in our previous report via molecular simulation. Furthermore, a substantial increase in anti-hemolytic activity was observed when the single bond (C1-C2) was replaced by a double bond (C1-C2) in the inhibitor molecule. This change was based on the decomposition of the ligand-residue interaction, which indicated that the double bond (C1-C2) in the inhibitors was required for their inhibition of LLO. The current MD simulation work provides insights into the mechanism by which the compounds inhibit LLO at the atomic level and will be useful for the development of new, selective LLO inhibitors.
细菌对现有抗生素的耐药性不断增加，使得发现新型有效的抗菌剂成为当务之急。先前的一份报告表明，李斯特菌溶血素O（LLO）是一种关键的毒力因子，并表明它是开发针对单核细胞增生李斯特菌感染的抗毒力药物的靶点。在本研究中，我们报告了通过溶血试验发现具有不同活性的LLO天然化合物抑制剂。抑制剂的作用机制与非瑟酮一致，非瑟酮是一种无抗菌活性的天然黄酮类化合物，我们在之前的报告中通过分子模拟证明了这一点。此外，当抑制剂分子中的单键（C1-C2）被双键（C1-C2）取代时，观察到抗溶血活性大幅增加。这种变化是基于配体-残基相互作用的分解，这表明抑制剂中的双键（C1-C2）是其抑制LLO所必需的。当前的分子动力学模拟工作在原子水平上深入了解了这些化合物抑制LLO的机制，将有助于开发新的、选择性的LLO抑制剂。
