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<p>Foodborne illnesses caused by pathogenic microorganisms, particularly <i>Salmonella</i> Typhimurium, are becoming increasingly prevalent. The enhanced virulence of this subspecies is primarily attributed to its strong biofilm-forming ability on food surfaces and contact materials. Biofilms not only enhance antibiotic resistance and environmental persistence but also increase pathogenicity, making infections difficult to eradicate. Biofilm formation is tightly regulated by proteins associated with adhesion, motility, and invasion. To identify the critical biofilm-regulating proteins, a comprehensive bioinformatics workflow was applied, integrating multiple tools, including PDB, UniProtKB, NCBI-BLAST, KEGG, Geptop 2.0, Cello2go, STRING, Cytoscape, InterPro, Prot-pi, and Schrödinger Maestro. This multi-step analysis identified four key proteins, FlgE, FabA, InvA, and LuxS, as central to biofilm regulation, each exhibiting strong interaction scores (&gt; 0.5). Citric acid was selected as a potential inhibitory compound due to its favourable interaction properties. Molecular docking demonstrated binding affinities of -3.9652, –3.874, –3.033, and –3.283&#xa0;kcal/mol for FlgE, FabA, InvA, and LuxS, respectively, with FlgE showing the strongest binding. Molecular dynamics simulations confirmed these results, revealing stable RMSD values (2.5–4.0&#xa0;Å for the protein and 4.5–63.8&#xa0;Å for the ligand) and consistent RMSF interactions across 31 amino acids (0.8–3.0&#xa0;Å). ADMET profiling further validated citric acid’s safe pharmacokinetic profile, supporting its suitability for human use. Experimental validation was conducted through qualitative MIC and MBIC assays, yielding values of 128&#xa0;µg/mL and 256&#xa0;µg/mL, respectively. Quantitative analysis by FE-SEM demonstrated significant disruption of the EPS matrix and biofilm structure in citric acid–treated samples compared to untreated controls after 60&#xa0;h of incubation. Collectively, these findings highlight citric acid as a promising natural antibiofilm agent against <i>Salmonella</i> Typhimurium. Its multi-target inhibitory potential provides valuable applications in food safety and supports the development of alternative antimicrobial strategies.</p>

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Computational investigation of citric acid as a potential inhibitor of Salmonella Typhimurium biofilm formation via regulatory protein cascade

  • 期刊论文

  • 发表日期：

    2025年11月19日

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  • Venkteshwar Yadav,
  • Dharm Pal,
  • Anil Kumar Poonia

摘要

Foodborne illnesses caused by pathogenic microorganisms, particularly Salmonella Typhimurium, are becoming increasingly prevalent. The enhanced virulence of this subspecies is primarily attributed to its strong biofilm-forming ability on food surfaces and contact materials. Biofilms not only enhance antibiotic resistance and environmental persistence but also increase pathogenicity, making infections difficult to eradicate. Biofilm formation is tightly regulated by proteins associated with adhesion, motility, and invasion. To identify the critical biofilm-regulating proteins, a comprehensive bioinformatics workflow was applied, integrating multiple tools, including PDB, UniProtKB, NCBI-BLAST, KEGG, Geptop 2.0, Cello2go, STRING, Cytoscape, InterPro, Prot-pi, and Schrödinger Maestro. This multi-step analysis identified four key proteins, FlgE, FabA, InvA, and LuxS, as central to biofilm regulation, each exhibiting strong interaction scores (> 0.5). Citric acid was selected as a potential inhibitory compound due to its favourable interaction properties. Molecular docking demonstrated binding affinities of -3.9652, –3.874, –3.033, and –3.283 kcal/mol for FlgE, FabA, InvA, and LuxS, respectively, with FlgE showing the strongest binding. Molecular dynamics simulations confirmed these results, revealing stable RMSD values (2.5–4.0 Å for the protein and 4.5–63.8 Å for the ligand) and consistent RMSF interactions across 31 amino acids (0.8–3.0 Å). ADMET profiling further validated citric acid’s safe pharmacokinetic profile, supporting its suitability for human use. Experimental validation was conducted through qualitative MIC and MBIC assays, yielding values of 128 µg/mL and 256 µg/mL, respectively. Quantitative analysis by FE-SEM demonstrated significant disruption of the EPS matrix and biofilm structure in citric acid–treated samples compared to untreated controls after 60 h of incubation. Collectively, these findings highlight citric acid as a promising natural antibiofilm agent against Salmonella Typhimurium. Its multi-target inhibitory potential provides valuable applications in food safety and supports the development of alternative antimicrobial strategies.