Department of Chemistry, University of Konstanz, D-78457 Konstanz, Germany.
ACS Chem Biol. 2013 Aug 16;8(8):1775-84. doi: 10.1021/cb400371r. Epub 2013 Jun 28.
The treatment of infections due to the opportunistic pathogen Pseudomonas aeruginosa is often difficult, as a consequence of bacterial biofilm formation. Such a protective environment shields the bacterium from host defense and antibiotic treatment and secures its survival. One crucial factor for maintenance of the biofilm architecture is the carbohydrate-binding lectin LecB. Here, we report the identification of potent mannose-based LecB inhibitors from a screening of four series of mannosides in a novel competitive binding assay for LecB. Cinnamide and sulfonamide derivatives are inhibitors of bacterial adhesion with up to a 20-fold increase in affinity to LecB compared to the natural ligand methyl mannoside. Because many lectins of the host require terminal saccharides (e.g., fucosides), such capped structures as reported here may offer a beneficial selectivity profile for the pathogenic lectin. Both classes of compounds show distinct binding modes at the protein, offering the advantage of a simultaneous development of two new lead structures as anti-pseudomonadal drugs with an anti-virulence mode of action.
由于机会性病原体铜绿假单胞菌的形成，其导致的感染的治疗常常具有难度，这是由于细菌生物膜的形成。这种保护环境使细菌免受宿主防御和抗生素治疗的影响，并确保其存活。维持生物膜结构的一个关键因素是碳水化合物结合凝集素 LecB。在这里，我们报告了从四种甘露糖系列的筛选中鉴定出的强效基于甘露糖的 LecB 抑制剂，该筛选是在新型竞争性 LecB 结合测定中进行的。肉桂酰胺和磺酰胺衍生物是细菌黏附抑制剂，与天然配体甲基甘露糖苷相比，对 LecB 的亲和力增加了 20 倍。由于宿主的许多凝集素需要末端糖（例如岩藻糖），因此这里报道的带有封端结构的化合物可能为致病性凝集素提供有益的选择性特征。这两类化合物在蛋白质上表现出不同的结合模式，提供了同时开发两种新的先导结构作为具有抗毒力作用模式的抗假单胞菌药物的优势。
