Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, 02114, USA.
Shriners Hospitals for Children, Boston, MA, 02114, USA.
Nat Commun. 2022 Aug 30;13(1):5103. doi: 10.1038/s41467-022-32833-9.
Intestinal barrier derangement allows intestinal bacteria and their products to translocate to the systemic circulation. Pseudomonas aeruginosa (PA) superimposed infection in critically ill patients increases gut permeability and leads to gut-driven sepsis. PA infections are challenging due to multi-drug resistance (MDR), biofilms, and/or antibiotic tolerance. Inhibition of the quorum-sensing transcriptional regulator MvfR(PqsR) is a desirable anti-PA anti-virulence strategy as MvfR controls multiple acute and chronic virulence functions. Here we show that MvfR promotes intestinal permeability and report potent anti-MvfR compounds, the N-Aryl Malonamides (NAMs), resulting from extensive structure-activity-relationship studies and thorough assessment of the inhibition of MvfR-controlled virulence functions. This class of anti-virulence non-native ligand-based agents has a half-maximal inhibitory concentration in the nanomolar range and strong target engagement. Using a NAM lead in monotherapy protects murine intestinal barrier function, abolishes MvfR-regulated small molecules, ameliorates bacterial dissemination, and lowers inflammatory cytokines. This study demonstrates the importance of MvfR in PA-driven intestinal permeability. It underscores the utility of anti-MvfR agents in maintaining gut mucosal integrity, which should be part of any successful strategy to prevent/treat PA infections and associated gut-derived sepsis in critical illness settings. NAMs provide for the development of crucial preventive/therapeutic monotherapy options against untreatable MDR PA infections.
肠道屏障功能紊乱可导致肠道细菌及其产物易位至全身循环。危重症患者合并铜绿假单胞菌（PA）感染会增加肠道通透性，导致肠道驱动性脓毒症。由于多药耐药（MDR）、生物膜和/或抗生素耐药性，PA 感染极具挑战性。抑制群体感应转录调节因子 MvfR（PqsR）是一种理想的抗 PA 抗毒力策略，因为 MvfR 控制多种急性和慢性毒力功能。本文中，我们证明了 MvfR 可促进肠道通透性，并报告了强效抗 MvfR 化合物 N-芳基丙二酰胺（NAMs），这是通过广泛的构效关系研究和对 MvfR 控制的毒力功能的抑制作用的全面评估而得到的。该类抗毒力非天然配体基药物的半数最大抑制浓度在纳摩尔范围内，且具有很强的靶标结合力。使用 NAM 单药治疗可保护小鼠肠道屏障功能，消除 MvfR 调节的小分子，改善细菌播散，并降低炎症细胞因子。本研究证明了 MvfR 在 PA 驱动的肠道通透性中的重要性。它强调了抗 MvfR 药物在维持肠道黏膜完整性方面的效用，这应该是预防/治疗危重症患者中不可治疗的 MDR PA 感染和相关肠道来源性脓毒症的任何成功策略的一部分。NAMs 为针对无法治疗的 MDR PA 感染的重要预防/治疗性单药治疗选择提供了可能。
