Benghezal Mohammed, Adam Eric, Lucas Aurore, Burn Christine, Orchard Michael G, Deuschel Christine, Valentino Emilio, Braillard Stéphanie, Paccaud Jean-Pierre, Cosson Pierre
Athelas SA, Chemin des Aulx 18, CH-1228 Plan-les-Ouates, Switzerland.
Cell Microbiol. 2007 May;9(5):1336-42. doi: 10.1111/j.1462-5822.2006.00877.x.
Antibiotic resistance continues to reduce the number of available antibiotics, increasing the need for novel antibacterial drugs. Since the seminal work of Sir Alexander Fleming, antibiotic identification has been based exclusively on the inhibition of bacterial growth in vitro. Recently, inhibitors of bacterial virulence which interfere with bacterial pathogenesis mechanisms have been proposed as an alternative to antibiotics, and a few were discovered using assays targeting specific virulence mechanisms. Here we designed a simple surrogate host model for the measurement of virulence and systematic discovery of anti-virulence molecules, based on the interaction of Tetrahymena pyriformis and Klebsiella pneumoniae cells. We screened a library of small molecules and identified several inhibitors of virulence. In a mouse pneumonia model we confirmed that an anti-virulence molecule displayed antibacterial activity against Klebsiella pneumoniae and Pseudomonas aeruginosa, by reducing dramatically the bacterial load in the lungs. This molecule did not inhibit bacterial growth in vitro but prevented biosynthesis of the Klebsiella capsule and lipopolysaccharides, a key requirement for virulence. Our results demonstrate that anti-virulence molecules represent an alternative to antibiotics and those can be discovered using non-animal host models.
抗生素耐药性持续降低了可用抗生素的数量，这使得对新型抗菌药物的需求不断增加。自亚历山大·弗莱明爵士的开创性工作以来，抗生素的鉴定一直完全基于体外对细菌生长的抑制作用。最近，干扰细菌致病机制的细菌毒力抑制剂已被提议作为抗生素的替代品，并且通过针对特定毒力机制的检测发现了一些此类抑制剂。在此，我们基于梨形四膜虫与肺炎克雷伯菌细胞的相互作用，设计了一个用于测量毒力和系统发现抗毒力分子的简单替代宿主模型。我们筛选了一个小分子文库并鉴定出了几种毒力抑制剂。在小鼠肺炎模型中，我们证实一种抗毒力分子通过大幅降低肺部细菌载量，对肺炎克雷伯菌和铜绿假单胞菌具有抗菌活性。该分子在体外不抑制细菌生长，但可阻止肺炎克雷伯菌荚膜和脂多糖的生物合成，而这是毒力的关键要素。我们的结果表明，抗毒力分子可作为抗生素的替代品，并且可以使用非动物宿主模型来发现它们。
