Abstract
To investigate the effects of tamoxifen on Staphylococcus aureus α-hemolysin channel (α-HL) in planar lipid bilayers with electrophysiological characterization and docking studies. Planar lipid bilayer membranes were prepared and α-HL (0.07 mg/mL) was added to the standard solution in cis compartment of the experimental chamber. All experiments were performed at room temperature using an Axopatch 200A amplifier in the voltage clamp mode. At pH 7.5, α-HL channels were usually in a high conductance ~4 nS and rarely switch to low conductance states. After the ion channel was incorporated in bilayer membrane, the tamoxifen was also added to the standard solution to the cis compartment. To docking studies, atomics coordinates for the α-HL heptameric channel was retrieved from PDB ID (7AHL) and the structure of tamoxifen was removed from the Pubchem, their coordinates were built and minimized with Avogadro software. The molecular docking experiments were performed using the Dockthor online portal. The tamoxifen inhibited (P < 0.05) α-HL channel conductance and it was a voltage-dependent manner. The three best docking solutions and the α-HL channel were evaluated, it was observed the connection mode with the highest affinity of interaction has a greater number of types of polar interaction. The residues present interactions of greater energy were 111 and 147 that form the remainders of the constriction in the channel of α-HL. The other conformers were accommodated in a region with more hydrophobic characteristics (valine 149). The mechanism of Staphylococcus aureus α-hemolysin inhibition by tamoxifen was blockade over the constriction of channel.
Highlights
The Staphylococcus aureus α-hemolysin channel (α-HL), importance in pathogenesis, is regarded as a virulence factor playing a role in infection (Bryant et al, 2019)
The large α-HL single-channel conductance ~4 nS in 4 M KCl, tamoxifen was assayed for its ability to block ion conductance through the pores formed in artificial membranes α-HL
Addition of about 100μM to the cis-side of the membrane switched the channel to a closed state similar to the ‘voltage-gated closed state’ seen commonly for α-HL at 100 mV and higher voltages
Summary
The Staphylococcus aureus α-hemolysin channel (α-HL), importance in pathogenesis, is regarded as a virulence factor playing a role in infection (Bryant et al, 2019). The α-HLs are exotoxins that create lytic pores in the host cell membrane They are recognized as being mainly for the development of invasive infections and are potential targets for antivirulence treatments (Liu et al, 2020). It is one of the first important bacterial and viral virulence factors which mechanism of action was disclosed (Fussle et al, 1981; Krasilnikov, et al, 1988) and is based on pore formation in lipid bilayer membranes. Molecular docking studies provided atomic level details on protein–ligand interactions These are expected to expand the knowledge on compounds molecular recognition by the heptameric pore, while tamoxifen is suggested as possible cotherapeutical agents for the treatment of infected patients. Tamoxifen on Staphylococcus aureus α-hemolysin (α-HL) currents and its molecular mechanism by docking studies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
