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<p>Cyclic diguanylate (c-di-GMP) is a central biofilm regulator in <i>Pseudomonas aeruginosa</i>, where increased intracellular levels promote biofilm formation and antibiotic tolerance. Targeting the c-di-GMP network may be a promising anti-biofilm approach, but most strategies studied so far aimed at eliminating surface-attached biofilms, while in vivo <i>P. aeruginosa</i> biofilms often occur as suspended aggregates. Here, the expression profile of c-di-GMP metabolism-related genes was analysed among 32 <i>P. aeruginosa</i> strains grown as aggregates in synthetic cystic fibrosis sputum. The diguanylate cyclase SiaD proved essential for auto-aggregation under in vivo-like conditions. Virtual screening predicted a high binding affinity of echinacoside towards the active site of SiaD. Echinacoside reduced c-di-GMP levels and aggregate sizes and potentiated tobramycin activity against aggregates in &gt;80% of strains tested. This synergism was also observed in <i>P. aeruginosa</i>-infected 3-D alveolar epithelial cells and murine lungs, demonstrating echinacoside’s potential as an adjunctive therapy for recalcitrant <i>P. aeruginosa</i> infections.</p>

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Echinacoside reduces intracellular c-di-GMP levels and potentiates tobramycin activity against Pseudomonas aeruginosa biofilm aggregates

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月7日

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  • Yu-Ming Cai,
  • Feng Hong,
  • Amber De Craemer,
  • Jacob George Malone,
  • Aurélie Crabbé,
  • Tom Coenye

摘要

Cyclic diguanylate (c-di-GMP) is a central biofilm regulator in Pseudomonas aeruginosa, where increased intracellular levels promote biofilm formation and antibiotic tolerance. Targeting the c-di-GMP network may be a promising anti-biofilm approach, but most strategies studied so far aimed at eliminating surface-attached biofilms, while in vivo P. aeruginosa biofilms often occur as suspended aggregates. Here, the expression profile of c-di-GMP metabolism-related genes was analysed among 32 P. aeruginosa strains grown as aggregates in synthetic cystic fibrosis sputum. The diguanylate cyclase SiaD proved essential for auto-aggregation under in vivo-like conditions. Virtual screening predicted a high binding affinity of echinacoside towards the active site of SiaD. Echinacoside reduced c-di-GMP levels and aggregate sizes and potentiated tobramycin activity against aggregates in >80% of strains tested. This synergism was also observed in P. aeruginosa-infected 3-D alveolar epithelial cells and murine lungs, demonstrating echinacoside’s potential as an adjunctive therapy for recalcitrant P. aeruginosa infections.