Ethacridine Targets Bacterial Biofilms in Diabetic Foot Ulcers: Multi-Target Mechanisms
Summary: This study elucidates ethacridine’s antibacterial mechanisms in diabetic foot ulcers (DFUs) through integrated network pharmacology, molecular docking, molecular dynamics (MD) simulation, and clinical RT-qPCR validation. Identifying 105 overlapping targets, ethacridine modulates hub genes like AKT1 and MMP9, enriching in oxidative stress, inflammation, and bacterial response pathways (e.g., AGE–RAGE, TNF, IL-17). Docking confirmed strong MMP9 binding (−9.8 kcal/mol), with MD simulations verifying complex stability. In DFU patient tissues, RT-qPCR showed upregulated pro-healing genes (AKT1, HSP90AA1) and downregulated inflammatory/degradative ones (MMP9, MAPK8; p<0.0001). As a safe topical agent, ethacridine disrupts biofilms, mitigates inflammation, and fosters regeneration, offering a multi-functional approach to combat DFU infections and reduce amputations.
Key Highlights:
- Network analysis identified 105 common targets, with 10 hubs (e.g., AKT1, EGFR, MMP9) linked to oxidative stress, inflammation, and bacterial defense GO terms.
- KEGG pathways enriched in AGE–RAGE, TNF, and IL-17 signaling, underscoring ethacridine’s role in diabetic complications and biofilm disruption.
- Molecular docking: Binding energies < −5.0 kcal/mol, strongest for MMP9 (−9.8 kcal/mol); MD simulation: Stable complex (RMSD < 2.4 Å, ~2 H-bonds).
- RT-qPCR in 20 DFU patients: Upregulated AKT1/HSP90AA1 (p<0.0001) for survival/angiogenesis; downregulated MMP9/MAPK8 (p<0.0001) for matrix preservation and inflammation control.
- Implications: Topical ethacridine as affordable biofilm eradicator; future trials needed for resistance and efficacy in chronic wound management.
Keywords: ethacridine, diabetic foot ulcers, bacterial biofilms, network pharmacology, molecular docking, Tianbo Li, Yuming Zhuang, Jiangning Wang