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.

作为单一物种和混合物种的生物膜，金黄色葡萄球菌和铜绿假单胞菌导致难以根除的慢性感染。在铜绿假单胞菌中，依赖于喹诺酮假单胞菌 (PQS) 的群体感应调节毒力和生物膜发育，这可以通过靶向转录调节因子 PqsR (MvfR) 的拮抗剂减弱。在这里，我们开发了一个包含 PqsR 激动剂和拮抗剂的喹唑啉酮 (QZN) 文库，用于单独与铜绿假单胞菌共培养以及与氨基糖苷类妥布霉素联合培养时对金黄色葡萄球菌的活性。PqsR 抑制剂 QZN 34杀死浮游革兰氏阳性菌，但不能杀死革兰氏阴性菌。QZN 34阻止了金黄色葡萄球菌生物膜的形成，严重破坏了已建立的金黄色葡萄球菌生物膜，并破坏了铜绿假单胞菌生物膜的发育。虽然铜绿假单胞菌在混合生物膜中保护金黄色葡萄球菌免受妥布霉素的侵害，但氨基糖苷类抗生素与 QZN 34的组合根除混合物种生物膜。QZN 34对革兰氏阳性菌的作用机制显示涉及膜破坏和跨膜电位的消散。