Dual action of benzaldehydes: Inhibiting quorum sensing and enhancing antibiotic efficacy for controlling Pseudomonas aeruginosa biofilms

Miguel M Leitão; Tatiana F Vieira; Sérgio F Sousa; Fernanda Borges; Manuel Simões; Anabela Borges

doi:10.1016/j.micpath.2024.106663

Dual action of benzaldehydes: Inhibiting quorum sensing and enhancing antibiotic efficacy for controlling Pseudomonas aeruginosa biofilms

Microb Pathog. 2024 Apr 26:191:106663. doi: 10.1016/j.micpath.2024.106663. Online ahead of print.

Authors

Miguel M Leitão¹, Tatiana F Vieira², Sérgio F Sousa², Fernanda Borges³, Manuel Simões⁴, Anabela Borges⁵

Affiliations

¹ LEPABE-Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465, Porto, Portugal; ALICE-Associate Laboratory for Innovation in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465, Porto, Portugal; CIQUP-IMS-Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal.
² LAQV/REQUIMTE, BioSIM-Department of Biomedicine, Faculty of Medicine, University of Porto, Rua Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.
³ CIQUP-IMS-Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal.
⁴ LEPABE-Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465, Porto, Portugal; ALICE-Associate Laboratory for Innovation in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465, Porto, Portugal; DEQ-Department of Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465, Porto, Portugal.
⁵ LEPABE-Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465, Porto, Portugal; ALICE-Associate Laboratory for Innovation in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465, Porto, Portugal; DEQ-Department of Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465, Porto, Portugal. Electronic address: apborges@fe.up.pt.

PMID: 38679246
DOI: 10.1016/j.micpath.2024.106663

Abstract

Quorum sensing (QS) has a central role in biofilm lifestyle and antimicrobial resistance, and disrupting these signaling pathways is a promising strategy to control bacterial pathogenicity and virulence. In this study, the efficacy of three structurally related benzaldehydes (4-hydroxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde (vanillin) and 4-hydroxy-3,5-dimethoxybenzaldehyde (syringaldehyde)) in disrupting the las and pqs systems of Pseudomonas aeruginosa was investigated using bioreporter strains and computational simulations. Additionally, these benzaldehydes were combined with tobramycin and ciprofloxacin antibiotics to evaluate their ability to increase antibiotic efficacy in preventing and eradicating P. aeruginosa biofilms. To this end, the total biomass, metabolic activity and culturability of the biofilm cells were determined. In vitro assays results indicated that the aromatic aldehydes have potential to inhibit the las and pqs systems by > 80 %. Molecular docking studies supported these findings, revealing the aldehydes binding in the same pocket as the natural ligands or receptor proteins (LasR, PQSA, PQSE, PQSR). Benzaldehydes were shown to act as virulence factor attenuators, with vanillin achieving a 48 % reduction in pyocyanin production. The benzaldehyde-tobramycin combination led not only to a 60 % reduction in biomass production but also to a 90 % reduction in the metabolic activity of established biofilms. A similar result was observed when benzaldehydes were combined with ciprofloxacin. 4-Hydroxybenzaldehyde demonstrated relevant action in increasing biofilm susceptibility to ciprofloxacin, resulting in a 65 % reduction in biomass. This study discloses, for the first time, that the benzaldehydes studied are potent QS inhibitors and also enhancers of antibiotics antibiofilm activity against P. aeruginosa.

Keywords: Antibiofilm activity; Antivirulence; Benzaldehydes; Dual combinations; P. aeruginosa biofilms; Quorum sensing inhibition.