Insights into structure and activity of natural compound inhibitors of pneumolysin.
Pneumolysin is the one of the major virulence factor of the bacterium Streptococcus pneumoniae. In previous report, it is shown that β-sitosterol, a natural compound without antimicrobial activity, is a potent antagonist of pneumolysin. Here, two new pneumolysin natural compound inhibitors, with differential activity, were discovered via haemolysis assay. To explore the key factor of the conformation for the inhibition activity, the interactions between five natural compound inhibitors with differential activity and pneumolysin were reported using molecular modelling, the potential of mean force profiles. Interestingly, it is found that incorporation of the single bond (C22-C23-C24-C25) to replace the double bond (hydrocarbon sidechain) improved the anti-haemolytic activity. In view of the molecular modelling, binding of the five inhibitors to the conserved loop region (Val372, Leu460, and Tyr461) of the cholesterol binding sites led to stable complex systems, which was consistent with the result of β-sitosterol. Owing to the single bond (C22-C23-C24-C25), campesterol and brassicasterol could form strong interactions with Val372 and show higher anti-haemolytic activity, which indicated that the single bond (C22-C23-C24-C25) in inhibitors was required for the anti-haemolytic activity. Overall, the current molecular modelling work provides a starting point for the development of rational design and higher activity pneumolysin inhibitors.
Department of Respiratory Medicine, The First Hospital of Jilin University, Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Hongen
H
Li
Department of Respiratory Medicine, The First Hospital of Jilin University, Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Xiaoran
X
Zhao
Department of Respiratory Medicine, The First Hospital of Jilin University, Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Xuming
X
Deng
Department of Respiratory Medicine, The First Hospital of Jilin University, Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Jianfeng
J
Wang
Department of Respiratory Medicine, The First Hospital of Jilin University, Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Meng
M
Song
Department of Respiratory Medicine, The First Hospital of Jilin University, Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Xiaodi
X
Niu
Department of Respiratory Medicine, The First Hospital of Jilin University, Key Laboratory of Zoonosis, Ministry of Education, Department of Food Quality and Safety, College of Veterinary Medicine, Jilin University, Changchun, China.
Liping
L
Peng
D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D002775:Cholestadienols / Q000737:chemistry / Q000494:pharmacology*; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010840:Phytosterols / Q000737:chemistry / Q000494:pharmacology*; D012756:Sheep / Q000097:blood; D013296:Streptococcus pneumoniae / Q000472:pathogenicity; D013301:Streptolysins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001426:Bacterial Proteins; D002775:Cholestadienols; D010840:Phytosterols; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; C003532:brassicasterol; C021273:campesterol; D002784:Cholesterol