Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada.
Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada.
Nat Commun. 2019 Jan 14;10(1):197. doi: 10.1038/s41467-018-08190-x.
Salmonella Typhimurium (S. Tm) establishes systemic infection in susceptible hosts by evading the innate immune response and replicating within host phagocytes. Here, we sought to identify inhibitors of intracellular S. Tm replication by conducting parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. We identify several compounds that inhibit Salmonella growth in the intracellular environment and in acidic, ion-limited media. We report on the antimicrobial activity of the psychoactive drug metergoline, which is specific against intracellular S. Tm. Screening an S. Tm deletion library in the presence of metergoline reveals hypersensitization of outer membrane mutants to metergoline activity. Metergoline disrupts the proton motive force at the bacterial cytoplasmic membrane and extends animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella.
鼠伤寒沙门氏菌（S. Typhimurium）通过逃避先天免疫反应并在宿主吞噬细胞内复制，在易感宿主中建立全身感染。在这里，我们通过针对在巨噬细胞模拟培养基和巨噬细胞内生长的 S. Typhimurium 进行平行化学筛选，试图确定抑制细胞内 S. Typhimurium 复制的抑制剂。我们发现了几种抑制沙门氏菌在细胞内环境和酸性、离子受限介质中生长的化合物。我们报告了精神药物麦角乙脲的抗菌活性，它对细胞内 S. Typhimurium 具有特异性。在麦角乙脲存在的情况下筛选 S. Typhimurium 缺失文库，揭示了外膜突变体对麦角乙脲活性的超敏反应。麦角乙脲破坏了细菌细胞质膜中的质子动力，并在全身性 S. Typhimurium 感染期间延长了动物的存活时间。这项工作突出了细胞内筛选对体内疗效的预测性质，并确定麦角乙脲是一种针对沙门氏菌的新型抗菌活性药物。
