A Pseudomonas aeruginosa PQS quorum-sensing system inhibitor with anti-staphylococcal activity sensitizes polymicrobial biofilms to tobramycin

Murray, Ewan J; Dubern, Jean-Frédéric; Chan, Weng C.; Chhabra, Siri Ram; Williams, Paul

Abstract

As single- and mixed-species biofilms, Staphylococcus aureus and Pseudomonas aeruginosa cause difficult-to-eradicate chronic infections. In P. aeruginosa, pseudomonas quinolone (PQS)-dependent quorum sensing regulates virulence and biofilm development that can be attenuated via antagonists targeting the transcriptional regulator PqsR (MvfR). Here, we exploited a quinazolinone (QZN) library including PqsR agonists and antagonists for their activity against S. aureus alone, when co-cultured with P. aeruginosa, and in combination with the aminoglycoside tobramycin. The PqsR inhibitor, QZN 34 killed planktonic Gram-positives but not Gram-negatives. QZN 34 prevented S. aureus biofilm formation, severely damaged established S. aureus biofilms, and perturbed P. aeruginosa biofilm development. Although P. aeruginosa protected S. aureus from tobramycin in mixed biofilms, the combination of aminoglycoside antibiotic with QZN 34 eradicated the mixed-species biofilm. The mechanism of action of QZN 34 toward Gram-positive bacteria is shown to involve membrane perturbation and dissipation of transmembrane potential.

Citation

Murray, E. J., Dubern, J., Chan, W. C., Chhabra, S. R., & Williams, P. (2022). A Pseudomonas aeruginosa PQS quorum-sensing system inhibitor with anti-staphylococcal activity sensitizes polymicrobial biofilms to tobramycin. Cell Chemical Biology, 29(7), 1187-1199.e6. https://doi.org/10.1016/j.chembiol.2022.02.007

• Journal Article Type: Article
• Acceptance Date: Jan 4, 2022
• Online Publication Date: Mar 7, 2022
• Publication Date: Jul 21, 2022
• Deposit Date: Jan 20, 2022
• Publicly Available Date: Mar 8, 2023
• Journal: Cell Chemical Biology
• Electronic ISSN: 2451-9448
• Publisher: Elsevier BV
• Peer Reviewed: Peer Reviewed
• Volume: 29
• Issue: 7
• Pages: 1187-1199.e6
• DOI: https://doi.org/10.1016/j.chembiol.2022.02.007
• Keywords: Clinical Biochemistry; Drug Discovery; Pharmacology; Molecular Biology; Molecular Medicine; Biochemistry
• Public URL: https://nottingham-repository.worktribe.com/output/7281762
• Publisher URL: https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(22)00088-5