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

  • NPJ Biofilms Microbiomes. 2025 Mar 7;11(1):40. doi: 10.1038/s41522-025-00673-2.
Yu-Ming Cai  1  2 ,  Feng Hong  3  4 ,  Amber De Craemer  5 ,  Jacob George Malone  6  7 ,  Aurélie Crabbé  5 ,  Tom Coenye  8
Affiliations
  • 1. Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium. [email protected].
  • 2. John Innes Centre, Norwich Research Park, Colney Lane, Norwich, UK. [email protected].
  • 3. Group of Microbiological Engineering and Biomedical Materials, College of Biological Science and Medical Engineering, Donghua University, North Ren Min Road 2999, 201620, Shanghai, China.
  • 4. National Advanced Functional Fiber Innovation Centre, Wu Jiang, Su Zhou, China.
  • 5. Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium.
  • 6. John Innes Centre, Norwich Research Park, Colney Lane, Norwich, UK.
  • 7. School of Biological Sciences, University of East Anglia, Norwich, UK.
  • 8. Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium. [email protected].
PMID: 40055321 DOI: 10.1038/s41522-025-00673-2
Abstract

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.

Products