Novel inhibitor discovery and the conformational analysis of inhibitors of listeriolysin O via protein-ligand modeling.
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.
Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Jianfeng
J
Wang
Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Xuan
X
Zhou
Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Shui
S
Liu
Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Gen
G
Li
Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Bing
B
Zhang
Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Xuming
X
Deng
Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Xiaodi
X
Niu
D000900:Anti-Bacterial Agents / Q000737:chemistry; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry*; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000648:ultrastructure*; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors* / Q000648:ultrastructure*; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping / Q000379:methods
D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D005419:Flavonoids; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; C038705:hlyA protein, Listeria monocytogenes