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<p><i>Enterococcus faecium</i>, a member of the ESKAPE pathogens, has become a significant clinical threat due to its rapidly increasing resistance to frontline antibiotics. This gram-positive bacterium has developed multidrug resistance through prolonged exposure to hospital environments, posing serious risks to immunocompromised patients. The present study aimed to identify novel therapeutic targets from the <i>E. faecium</i> genome and to explore the potential of marine natural products as anti-quorum sensing agents. A comprehensive subtractive proteomics pipeline incorporating non-human homology, essentiality, subcellular localization, druggability, and pathway uniqueness identified the accessory gene regulator A protein (AgrA) as a key target involved in quorum sensing, biofilm formation, and virulence. Following structural quality assessment, a hierarchy-based virtual screening of MNPs from the CMNPD and SPECS natural product libraries was carried out to identify potential AgrA inhibitors. The virtual screening workflow shortlisted three promising MNPs (CMNPD6428, CMNPD30814, and SPECS AE-765) with favourable binding affinities and pharmacokinetic properties. Docking scores ranged from − 7.46 to − 8.01&#xa0;kcal/mol, and MM/GBSA binding free energy calculations (≤ − 50&#xa0;kcal/mol) further supported their strong interactions. Pharmacokinetic evaluation indicated acceptable safety profiles. Density functional theory analysis confirmed the chemical stability and reactivity of the compounds through HOMO–LUMO energy gap assessment. Finally, 500&#xa0;ns molecular dynamics simulations and principal component analysis–based free energy landscape mapping validated the structural stability and sustained binding of the identified MNPs within the AgrA binding pocket. Overall, this study highlights three promising MNPs as potential anti-quorum sensing leads against <i>E. faecium</i>, offering a foundation for future therapeutic development.</p> Graphical abstract <p></p>

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Subtractive proteomics-driven identification of AgrA and structure-guided discovery of phytochemical and marine natural products as novel anti-quorum sensing therapeutic leads against Enterococcus faecium

  • 期刊论文

  • 发表日期：

    2026年4月26日

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  • Pradeep Kumar Sriram,
  • Manikandan Jayaraman,
  • Maharaja Muthuvairam Subbulakshmi,
  • Shaslinah Nathar,
  • Dhamodharan Prabhu,
  • Jeyakanthan Jeyaraman

摘要

Enterococcus faecium, a member of the ESKAPE pathogens, has become a significant clinical threat due to its rapidly increasing resistance to frontline antibiotics. This gram-positive bacterium has developed multidrug resistance through prolonged exposure to hospital environments, posing serious risks to immunocompromised patients. The present study aimed to identify novel therapeutic targets from the E. faecium genome and to explore the potential of marine natural products as anti-quorum sensing agents. A comprehensive subtractive proteomics pipeline incorporating non-human homology, essentiality, subcellular localization, druggability, and pathway uniqueness identified the accessory gene regulator A protein (AgrA) as a key target involved in quorum sensing, biofilm formation, and virulence. Following structural quality assessment, a hierarchy-based virtual screening of MNPs from the CMNPD and SPECS natural product libraries was carried out to identify potential AgrA inhibitors. The virtual screening workflow shortlisted three promising MNPs (CMNPD6428, CMNPD30814, and SPECS AE-765) with favourable binding affinities and pharmacokinetic properties. Docking scores ranged from − 7.46 to − 8.01 kcal/mol, and MM/GBSA binding free energy calculations (≤ − 50 kcal/mol) further supported their strong interactions. Pharmacokinetic evaluation indicated acceptable safety profiles. Density functional theory analysis confirmed the chemical stability and reactivity of the compounds through HOMO–LUMO energy gap assessment. Finally, 500 ns molecular dynamics simulations and principal component analysis–based free energy landscape mapping validated the structural stability and sustained binding of the identified MNPs within the AgrA binding pocket. Overall, this study highlights three promising MNPs as potential anti-quorum sensing leads against E. faecium, offering a foundation for future therapeutic development.

Graphical abstract