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Molecular modeling reveals the novel inhibition mechanism and binding mode of three natural compounds to staphylococcal α-hemolysin.

Qiu J, Wang D, Zhang Y, Dong J, Wang J, Niu X - PLoS ONE (2013)

Bottom Line: This was completed using conventional Molecular Dynamics (MD) simulations.This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay.This study can facilitate the design of new antibacterial drugs against S. aureus.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.

ABSTRACT
α-Hemolysin (α-HL) is a self-assembling, channel-forming toxin that is produced as a soluble monomer by Staphylococcus aureus strains. Until now, α-HL has been a significant virulence target for the treatment of S. aureus infection. In our previous report, we demonstrated that some natural compounds could bind to α-HL. Due to the binding of those compounds, the conformational transition of α-HL from the monomer to the oligomer was blocked, which resulted in inhibition of the hemolytic activity of α-HL. However, these results have not indicated how the binding of the α-HL inhibitors influence the conformational transition of the whole protein during the oligomerization process. In this study, we found that three natural compounds, Oroxylin A 7-O-glucuronide (OLG), Oroxin A (ORA), and Oroxin B (ORB), when inhibiting the hemolytic activity of α-HL, could bind to the "stem" region of α-HL. This was completed using conventional Molecular Dynamics (MD) simulations. By interacting with the novel binding sites of α-HL, the ligands could form strong interactions with both sides of the binding cavity. The results of the principal component analysis (PCA) indicated that because of the inhibitors that bind to the "stem" region of α-HL, the conformational transition of α-HL from the monomer to the oligomer was restricted. This caused the inhibition of the hemolytic activity of α-HL. This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay. This study can facilitate the design of new antibacterial drugs against S. aureus.

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Hemolytic activity of α-HL after treating with increasing concentrations (µg/ml) of OLG, ORA and ORB. “+” indicates the positive control while “-” indicates the negative control.
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pone-0080197-g001: Hemolytic activity of α-HL after treating with increasing concentrations (µg/ml) of OLG, ORA and ORB. “+” indicates the positive control while “-” indicates the negative control.

Mentions: Thus, α-HL has been shown to be a promising target for the development of anti-S. aureus agents. Screening for compounds that potentially inhibit α-HL function would facilitate the process of developing anti-α-HL drugs. In this study, we identify three compounds (OLG, ORA and ORB) that share structural similarity and could significantly suppress the hemolytic function of α-HL by screening with natural compounds (Fig. 1andTable 1). The 50% inhibitory concentrations were 0.73, 6.69 and 13.15 µg/ml for OLG, ORA and ORB, respectively. OLG displayed the strongest inhibitory action among these three compounds.


Molecular modeling reveals the novel inhibition mechanism and binding mode of three natural compounds to staphylococcal α-hemolysin.

Qiu J, Wang D, Zhang Y, Dong J, Wang J, Niu X - PLoS ONE (2013)

Hemolytic activity of α-HL after treating with increasing concentrations (µg/ml) of OLG, ORA and ORB. “+” indicates the positive control while “-” indicates the negative control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842302&req=5

pone-0080197-g001: Hemolytic activity of α-HL after treating with increasing concentrations (µg/ml) of OLG, ORA and ORB. “+” indicates the positive control while “-” indicates the negative control.
Mentions: Thus, α-HL has been shown to be a promising target for the development of anti-S. aureus agents. Screening for compounds that potentially inhibit α-HL function would facilitate the process of developing anti-α-HL drugs. In this study, we identify three compounds (OLG, ORA and ORB) that share structural similarity and could significantly suppress the hemolytic function of α-HL by screening with natural compounds (Fig. 1andTable 1). The 50% inhibitory concentrations were 0.73, 6.69 and 13.15 µg/ml for OLG, ORA and ORB, respectively. OLG displayed the strongest inhibitory action among these three compounds.

Bottom Line: This was completed using conventional Molecular Dynamics (MD) simulations.This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay.This study can facilitate the design of new antibacterial drugs against S. aureus.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.

ABSTRACT
α-Hemolysin (α-HL) is a self-assembling, channel-forming toxin that is produced as a soluble monomer by Staphylococcus aureus strains. Until now, α-HL has been a significant virulence target for the treatment of S. aureus infection. In our previous report, we demonstrated that some natural compounds could bind to α-HL. Due to the binding of those compounds, the conformational transition of α-HL from the monomer to the oligomer was blocked, which resulted in inhibition of the hemolytic activity of α-HL. However, these results have not indicated how the binding of the α-HL inhibitors influence the conformational transition of the whole protein during the oligomerization process. In this study, we found that three natural compounds, Oroxylin A 7-O-glucuronide (OLG), Oroxin A (ORA), and Oroxin B (ORB), when inhibiting the hemolytic activity of α-HL, could bind to the "stem" region of α-HL. This was completed using conventional Molecular Dynamics (MD) simulations. By interacting with the novel binding sites of α-HL, the ligands could form strong interactions with both sides of the binding cavity. The results of the principal component analysis (PCA) indicated that because of the inhibitors that bind to the "stem" region of α-HL, the conformational transition of α-HL from the monomer to the oligomer was restricted. This caused the inhibition of the hemolytic activity of α-HL. This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay. This study can facilitate the design of new antibacterial drugs against S. aureus.

Show MeSH
Related in: MedlinePlus