Quorum Sensing Inhibitors Increase the Susceptibility of Bacterial Biofilms to Antibiotics In Vitro and In Vivo

TLDR

Quorum sensing’s role in biofilm development and resistance remains unclear, but quorum‑sensing inhibitors have been proposed as a potential antibiofilm strategy. This study examined whether quorum‑sensing inhibitors enhance the susceptibility of bacterial biofilms to conventional antimicrobial agents. The investigators used baicalin hydrate, cinnamaldehyde, and hamamelitannin to inhibit acyl‑homoserine lactone and peptide quorum‑sensing systems in *Pseudomonas aeruginosa*, *Burkholderia cepacia* complex, and *Staphylococcus aureus*, and tested these inhibitors alone or with tobramycin, clindamycin, or vancomycin in vitro and in vivo biofilm models, including *Galleria mellonella*, *Caenorhabditis elegans*, and a mouse pulmonary infection model. Combining antibiotics with quorum‑sensing inhibitors generally increased bacterial killing and host survival compared to antibiotics alone, as shown by higher survival rates in *Galleria mellonella* and *Caenorhabditis elegans* and a greater reduction of lung bacterial load in mice infected with *Burkholderia cenocepacia*.

Abstract

ABSTRACT Although the exact role of quorum sensing (QS) in various stages of biofilm formation, maturation, and dispersal and in biofilm resistance is not entirely clear, the use of QS inhibitors (QSI) has been proposed as a potential antibiofilm strategy. We have investigated whether QSI enhance the susceptibility of bacterial biofilms to treatment with conventional antimicrobial agents. The QSI used in our study target the acyl-homoserine lactone-based QS system present in Pseudomonas aeruginosa and Burkholderia cepacia complex organisms (baicalin hydrate, cinnamaldehyde) or the peptide-based system present in Staphylococcus aureus (hamamelitannin). The effect of tobramycin ( P. aeruginosa , B. cepacia complex) and clindamycin or vancomycin ( S. aureus ), alone or in combination with QSI, was evaluated in various in vitro and in vivo biofilm model systems, including two invertebrate models and one mouse pulmonary infection model. In vitro the combined use of an antibiotic and a QSI generally resulted in increased killing compared to killing by an antibiotic alone, although reductions were strain and model dependent. A significantly higher fraction of infected Galleria mellonella larvae and Caenorhabditis elegans survived infection following combined treatment, compared to treatment with an antibiotic alone. Finally, the combined use of tobramycin and baicalin hydrate reduced the microbial load in the lungs of BALB/c mice infected with Burkholderia cenocepacia more than tobramycin treatment alone. Our data suggest that QSI may increase the success of antibiotic treatment by increasing the susceptibility of bacterial biofilms and/or by increasing host survival following infection.