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.

作为单一和混合物种生物膜，金黄色葡萄球菌和铜绿假单胞菌会导致难以根除的慢性感染。在铜绿假单胞菌中，喹诺酮假单胞菌 (PQS) 依赖性群体感应调节毒力和生物膜发育，可通过针对转录调节因子 PqsR (MvfR) 的拮抗剂减弱这种毒力和生物膜的形成。在这里，我们利用了包括 PqsR 激动剂和拮抗剂的喹唑啉酮 (QZN) 文库，当与铜绿假单胞菌共培养以及与氨基糖苷妥布霉素组合时，它们单独对抗金黄色葡萄球菌具有活性。 PqsR 抑制剂 QZN 34可杀死浮游革兰氏阳性菌，但不能杀死革兰氏阴性菌。 QZN 34阻止金黄色葡萄球菌生物膜的形成，严重破坏已建立的金黄色葡萄球菌生物膜，并扰乱铜绿假单胞菌生物膜的发育。尽管铜绿假单胞菌保护金黄色葡萄球菌免受混合生物膜中妥布霉素的侵害，但氨基糖苷类抗生素与 QZN 34的组合消除了混合物种生物膜。 QZN 34对革兰氏阳性菌的作用机制显示涉及膜扰动和跨膜电位耗散。