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<p>Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection, leading to widespread inflammation, immune dysfunction, and multi-organ failure. <i>Staphylococcus aureus</i> is a major etiological agent of sepsis among ESKAPE pathogens, largely due to its secretion of alpha-hemolysin (α-HL), a pore-forming exotoxin that disrupts host membranes through oligomerization. α-HL induces hemolysis, vascular leakage, and immune cell lysis, making it a critical virulence determinant and an attractive target for anti-virulence therapeutics. This study employed structure-based virtual screening of 107 natural phenolic derivatives from PubChem using Schrödinger’s LigPrep workflow. Eight compounds showed favorable ADMET properties, and Cianidanol displayed the strongest affinity toward α-HL (− 34.48&#xa0;kcal/mol). MM-GBSA calculations and 100&#xa0;ns molecular dynamics simulations confirmed the stability of the α-HL–Cianidanol complex, characterized by low RMSD values and persistent hydrogen bonding. Structural analysis revealed that Cianidanol targets the β-subunit interface, sterically hindering oligomerization and preventing heptameric pore formation. To evaluate the broader anti-virulence potential, comparative in silico studies were conducted against additional S. aureus β-pore-forming toxins, including Panton–Valentine leukocidin (PVL), γ-hemolysin, and enterotoxin. Cianidanol exhibited favorable docking scores and stable MD profiles across all three toxins, indicating its ability to interact with conserved structural pockets essential for pore assembly. Overall, these findings suggest that Cianidanol not only inhibits α-HL–mediated cytotoxicity but may also act as a broad-spectrum inhibitor of multiple staphylococcal pore-forming toxins, highlighting its potential as a promising anti-virulence candidate for preventing <i>S. aureus</i>-induced sepsis.</p>

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Structure-based identification of natural inhibitors targeting alpha-hemolysin to prevent pore formation in Staphylococcus aureus-induced sepsis

  • 期刊论文

  • 发表日期：

    2026年3月4日

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  • Aman Singh,
  • Pratima Gupta

摘要

Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection, leading to widespread inflammation, immune dysfunction, and multi-organ failure. Staphylococcus aureus is a major etiological agent of sepsis among ESKAPE pathogens, largely due to its secretion of alpha-hemolysin (α-HL), a pore-forming exotoxin that disrupts host membranes through oligomerization. α-HL induces hemolysis, vascular leakage, and immune cell lysis, making it a critical virulence determinant and an attractive target for anti-virulence therapeutics. This study employed structure-based virtual screening of 107 natural phenolic derivatives from PubChem using Schrödinger’s LigPrep workflow. Eight compounds showed favorable ADMET properties, and Cianidanol displayed the strongest affinity toward α-HL (− 34.48 kcal/mol). MM-GBSA calculations and 100 ns molecular dynamics simulations confirmed the stability of the α-HL–Cianidanol complex, characterized by low RMSD values and persistent hydrogen bonding. Structural analysis revealed that Cianidanol targets the β-subunit interface, sterically hindering oligomerization and preventing heptameric pore formation. To evaluate the broader anti-virulence potential, comparative in silico studies were conducted against additional S. aureus β-pore-forming toxins, including Panton–Valentine leukocidin (PVL), γ-hemolysin, and enterotoxin. Cianidanol exhibited favorable docking scores and stable MD profiles across all three toxins, indicating its ability to interact with conserved structural pockets essential for pore assembly. Overall, these findings suggest that Cianidanol not only inhibits α-HL–mediated cytotoxicity but may also act as a broad-spectrum inhibitor of multiple staphylococcal pore-forming toxins, highlighting its potential as a promising anti-virulence candidate for preventing S. aureus-induced sepsis.