Yakobi Sinethemba H, Ramaloko Winnie, Maningi Nontuthuko E
Microbiology Department, School of Life Sciences, University of KwaZulu Natal, Durban, South Africa.
Biochem Biophys Rep. 2025 Jul 1;43:102124. doi: 10.1016/j.bbrep.2025.102124. eCollection 2025 Sep.
The emergence of antibiotic-resistant biofilms necessitates novel therapeutic strategies targeting virulence pathways. In this study the structural mechanisms underlying the differential anti-biofilm efficacy of epigallocatechin gallate (EGCG) and furanone derivatives through integrative computational approaches were annotated. Molecular dynamics simulations reveal EGCG stabilizes the c-di-GMP receptor PA0012 via multivalent interactions (Δ = -65.3 kcal/mol), maintaining low structural fluctuations (RMSF <3 Å) and persistent contacts with catalytic residues (ARG9, ASP75). In contrast, furanone binding induces receptor destabilization (RMSF >6 Å) due to sparse interaction networks (1.2 contacts/nm vs EGCG's 4.8 contacts/nm), rationalizing its limited biofilm dispersal capacity. EGCG's superior binding correlates with experimental IC values (75 μg/mL biofilm inhibition vs furanone's 15 μM) through: (1) bidentate hydrogen bonding, (2) π-cation stacking, and (3) optimal interfacial hydrophobicity. These findings establish a structure-dynamics-activity relationship for PA0012-targeted inhibitors, proposing EGCG-inspired scaffolds with enhanced pharmacokinetics as next-generation anti-biofilm therapeutics.
抗生素耐药生物膜的出现需要针对毒力途径的新型治疗策略。在本研究中，通过综合计算方法阐明了表没食子儿茶素没食子酸酯（EGCG）和呋喃酮衍生物抗生物膜疗效差异背后的结构机制。分子动力学模拟表明，EGCG通过多价相互作用稳定c-di-GMP受体PA0012（Δ = -65.3 kcal/mol），保持低结构波动（RMSF <3 Å）并与催化残基（ARG9、ASP75）持续接触。相比之下，呋喃酮的结合由于稀疏的相互作用网络（1.2个接触/纳米，而EGCG为4.8个接触/纳米）导致受体不稳定（RMSF >6 Å），这解释了其有限的生物膜分散能力。EGCG优异的结合能力通过以下方式与实验IC值相关（75 μg/mL生物膜抑制率对比呋喃酮为15 μM）：（1）双齿氢键，（2）π-阳离子堆积，以及（3）最佳界面疏水性。这些发现建立了针对PA0012抑制剂的结构-动力学-活性关系，提出以EGCG为灵感的具有增强药代动力学的支架作为下一代抗生物膜治疗药物。
