Cell Chemical Biology
Volume 29, Issue 7, 21 July 2022, Pages 1187-1199.e6
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Article
A Pseudomonas aeruginosa PQS quorum-sensing system inhibitor with anti-staphylococcal activity sensitizes polymicrobial biofilms to tobramycin

https://doi.org/10.1016/j.chembiol.2022.02.007Get rights and content
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Highlights

  • QZNs inhibit PQS-dependent quorum sensing and reduce biofilm formation in Pseudomonas aeruginosa

  • A subset of QZNs is bactericidal for planktonic Staphylococcus aureus and severely damages biofilms

  • In mixed species biofilms, P. aeruginosa protects S. aureus from tobramycin

  • Tobramycin plus QZN eradicates mixed P. aeruginosa and S. aureus biofilms

Summary

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.

Keywords

Staphylococcus aureus
Pseudomonas aeruginosa
biofilms
quinazolinone
antimicrobials
quorum sensing
PqsR
MvfR

Data and code availability

The published article includes all biological data generated during this study. This study did not generate code. All data reported in this paper will be shared by the lead contact upon request.

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3

These authors contributed equally

4

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