Wu Yi, Wen Fulong, Gou Shiyi, Ran Qiman, Chu Yiwen, Ma Wenbo, Zhao Kelei
Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, School of Pharmacy, Chengdu University, Chengdu, Sichuan, China.
Virulence. 2025 Dec;16(1):2479103. doi: 10.1080/21505594.2025.2479103. Epub 2025 Mar 19.
As antibiotic resistance escalates into a global health crisis, novel therapeutic approaches against infectious diseases are in urgent need. , an adaptable opportunistic pathogen, poses substantial challenges in treating a range of infections. The quorum-sensing (QS) system plays a pivotal role in orchestrating the production of a large set of virulence factors in a cell density-dependent manner, and the anti-virulence strategy targeting QS may show huge potential. Here, we present a comprehensive investigation into the potential of the synthesized compound 3-(benzo[d][1,3]dioxol-4-yl)oxazolidin-2-one (OZDO, CHNO) as a QS inhibitor to curb the virulence of . By employing an integrated approach encompassing screening, and functional identification, we elucidated the multifaceted effects of OZDO. Molecular docking predicted that OZDO interfered with three core regulatory proteins of QS system. Notably, OZDO exhibited significant inhibition on the production of pyocyanin, rhamnolipid and extracellular proteases, biofilm formation, and cell motilities of . Transcriptomic analysis and quantitative real-time PCR displayed the down-regulation of QS-controlled genes in OZDO-treated PAO1, reaffirming the QS-inhibition activity of OZDO. assessments using a -infection model demonstrated OZDO mitigated pathogenicity, particularly against the hypervirulent strain PA14. Moreover, OZDO in combination with polymyxin B and aztreonam presented a promising avenue for innovative anti-infective therapy. Our study sheds light on the multifaceted potential of OZDO as an anti-virulence agent and its significance in combating -associated infections.
随着抗生素耐药性升级为全球健康危机，针对传染病的新型治疗方法亟待开发。铜绿假单胞菌作为一种适应性强的机会致病菌，在治疗一系列感染方面带来了巨大挑战。群体感应（QS）系统在以细胞密度依赖性方式协调大量毒力因子的产生中起着关键作用，针对QS的抗毒力策略可能具有巨大潜力。在此，我们对合成化合物3-（苯并[d][1,3]二氧杂环戊烯-4-基）恶唑烷-2-酮（OZDO，C₉H₉NO₃）作为一种QS抑制剂来抑制铜绿假单胞菌毒力的潜力进行了全面研究。通过采用包括筛选、鉴定和功能识别在内的综合方法，我们阐明了OZDO的多方面作用。分子对接预测OZDO干扰了铜绿假单胞菌QS系统的三种核心调节蛋白。值得注意的是，OZDO对铜绿假单胞菌的绿脓菌素、鼠李糖脂和细胞外蛋白酶的产生、生物膜形成以及细胞运动性表现出显著抑制作用。转录组分析和定量实时PCR显示在经OZDO处理的PAO1中QS控制基因的下调，再次证实了OZDO的QS抑制活性。使用铜绿假单胞菌感染模型的评估表明OZDO减轻了铜绿假单胞菌的致病性，特别是对高毒力菌株PA14。此外，OZDO与多粘菌素B和氨曲南联合使用为创新抗感染治疗提供了一条有前景的途径。我们的研究揭示了OZDO作为一种抗毒力剂的多方面潜力及其在对抗铜绿假单胞菌相关感染中的意义。
