Inhibitors of bacterial virulence identified in a surrogate host model
Inhibitors of bacterial virulence identified in a surrogate host model
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DOI：
10.1111/j.1462-5822.2006.00877.x
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发表时间：
2007-05-01
影响因子：
3.4
通讯作者：
Cosson, Pierre
中科院分区：
文献类型：
--
作者：
Benghezal, Mohammed;Adam, Eric;Cosson, Pierre
抗生素耐药性继续减少可用抗生素的数量，增加了对新型抗菌药物的需求。自从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细菌生长的抑制。最近，已经提出了干扰细菌致病机制的细菌毒力抑制剂作为抗生素的替代品，并且使用针对特定毒力机制的测定发现了一些。在这里，我们设计了一个简单的替代宿主模型的毒力和系统的发现抗毒力分子的测量，基于梨形四膜虫和肺炎克雷伯氏菌细胞的相互作用。我们筛选了一个小分子库，并确定了几个毒力抑制剂。在小鼠肺炎模型中，我们证实了一种抗毒力分子通过显著降低肺部细菌负荷，对肺炎克雷伯氏菌和铜绿假单胞菌显示出抗菌活性。该分子在体外不抑制细菌生长，但阻止了克雷伯氏菌荚膜和脂多糖的生物合成，这是毒力的关键要求。我们的研究结果表明，抗毒力分子代表了抗生素的替代品，并且可以使用非动物宿主模型发现。
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.