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<p><i>Staphylococcus aureus</i> is a major Gram-positive pathogen responsible for diverse infections, largely mediated by virulence factors such as α-hemolysin (Hla), a pore-forming cytotoxin that contributes to host cell damage and disease severity. Targeting virulence determinants rather than bacterial viability has emerged as a promising strategy to combat antimicrobial resistance. In the present study, we combined experimental and structure-based computational approaches to identify potential small-molecule suppressors of Hla. Fifty clinical isolates of <i>S. aureus</i> were obtained from skin and pus samples and confirmed using culture, microscopic, and biochemical analyses. α-Hemolysin was extracted from culture supernatants, purified through chromatographic techniques, and verified by UV-Vis spectrophotometry and SDS-PAGE, which revealed a characteristic band at approximately 33&#xa0;kDa. Structure-guided virtual screening of a compound library identified five candidate inhibitors with predicted binding energies ranging from − 10.8 to -4.2&#xa0;kcal/mol. Among these, two fungal secondary metabolites 4,5-dioxo-5-phenylpentanamide and (1-aminoethoxy)methyl hydrogen carbonate previously purified and structurally characterized in our laboratory were selected for experimental evaluation. Treatment of <i>S. aureus</i> cultures with these compounds resulted in concentration-dependent suppression of hemolytic phenotypes and reduced extracellular Hla abundance under culture conditions, with the cyclic metabolite exhibiting a stronger effect. These findings suggest interference with toxin production or extracellular availability rather than direct enzymatic neutralization. Overall, this study demonstrates a combined in silico- in vitro workflow for identifying anti-virulence candidates and highlights fungal secondary metabolites as promising scaffolds for further development of Hla-targeted therapeutic strategies.</p>

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Structure Guided Identification of Small Molecule Inhibitors Targeting Staphylococcus aureus α-Hemolysin

  • 期刊论文

  • 发表日期：

    2026年3月28日

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  • Saeed Ullah Khattak,
  • Nida Raza,
  • Mawahib Ahmed,
  • Ayesha Saleem,
  • Muhammad Salim,
  • Sajjad Ahmad

摘要

Staphylococcus aureus is a major Gram-positive pathogen responsible for diverse infections, largely mediated by virulence factors such as α-hemolysin (Hla), a pore-forming cytotoxin that contributes to host cell damage and disease severity. Targeting virulence determinants rather than bacterial viability has emerged as a promising strategy to combat antimicrobial resistance. In the present study, we combined experimental and structure-based computational approaches to identify potential small-molecule suppressors of Hla. Fifty clinical isolates of S. aureus were obtained from skin and pus samples and confirmed using culture, microscopic, and biochemical analyses. α-Hemolysin was extracted from culture supernatants, purified through chromatographic techniques, and verified by UV-Vis spectrophotometry and SDS-PAGE, which revealed a characteristic band at approximately 33 kDa. Structure-guided virtual screening of a compound library identified five candidate inhibitors with predicted binding energies ranging from − 10.8 to -4.2 kcal/mol. Among these, two fungal secondary metabolites 4,5-dioxo-5-phenylpentanamide and (1-aminoethoxy)methyl hydrogen carbonate previously purified and structurally characterized in our laboratory were selected for experimental evaluation. Treatment of S. aureus cultures with these compounds resulted in concentration-dependent suppression of hemolytic phenotypes and reduced extracellular Hla abundance under culture conditions, with the cyclic metabolite exhibiting a stronger effect. These findings suggest interference with toxin production or extracellular availability rather than direct enzymatic neutralization. Overall, this study demonstrates a combined in silico- in vitro workflow for identifying anti-virulence candidates and highlights fungal secondary metabolites as promising scaffolds for further development of Hla-targeted therapeutic strategies.