Klebsiella pneumoniae is an important pathogen causing difficult-to-treat urinary tract infections (UTIs). Over 1.5 million women per year suffer from recurrent UTI, reducing quality of life and causing substantial morbidity and mortality, especially in the hospital setting. Uropathogenic E. coli (UPEC) is the most prevalent cause of UTI. Like UPEC, K. pneumoniae relies on type 1 pili, tipped with the mannose-binding adhesin FimH, to cause cystitis. However, K. pneumoniae FimH is a poor binder of mannose, despite a mannose-binding pocket identical to UPEC FimH. FimH is composed of two domains that are in an equilibrium between tense (low-affinity) and relaxed (high-affinity) conformations. Substantial interdomain interactions in the tense conformation yield a low-affinity, deformed mannose-binding pocket, while domain–domain interactions are broken in the relaxed state, resulting in a high-affinity binding pocket. Using crystallography, we identified the structural basis by which domain–domain interactions direct the conformational equilibrium of K. pneumoniae FimH, which is strongly shifted toward the low-affinity tense state. Removal of the pilin domain restores mannose binding to the lectin domain, thus showing that poor mannose binding by K. pneumoniae FimH is not an inherent feature of the mannose-binding pocket. Phylogenetic analyses of K. pneumoniae genomes found that FimH sequences are highly conserved. However, we surveyed a collection of K. pneumoniae isolates from patients with long-term indwelling catheters and identified isolates that possessed relaxed higher-binding FimH variants, which increased K. pneumoniae fitness in bladder infection models, suggesting that long-term residence within the urinary tract may select for higher-binding FimH variants.

中文翻译：

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肺炎克雷伯菌 FimH 中的构象集合影响尿路发病机制


肺炎克雷伯菌是导致难以治疗的尿路感染 （UTI） 的重要病原体。每年有超过 150 万妇女患有复发性尿路感染，这降低了生活质量并导致了大量发病率和死亡率，尤其是在医院环境中。尿路致病性大肠杆菌 （UPEC） 是 UTI 最普遍的原因。与 UPEC 一样，肺炎克雷伯菌依靠 1 型菌毛（尖端有甘露糖结合粘附素 FimH）引起膀胱炎。然而，肺炎克雷伯菌 FimH 是甘露糖的不良结合物，尽管甘露糖结合口袋与 UPEC FimH 相同。FimH 由两个结构域组成，这两个结构域在紧张（低亲和力）和松弛（高亲和力）构象之间处于平衡状态。紧张构象中的大量结构域间相互作用产生低亲和力、变形的甘露糖结合口袋，而结构域-结构域相互作用在松弛状态下断开，导致高亲和力结合口袋。使用晶体学，我们确定了结构域-结构域相互作用指导肺炎克雷伯菌 FimH 构象平衡的结构基础，该平衡强烈地转向低亲和力紧张态。去除 pilin 结构域可恢复甘露糖与凝集素结构域的结合，从而表明肺炎克雷伯菌 FimH 结合不良的甘露糖结合不是甘露糖结合口袋的固有特征。肺炎克雷伯菌基因组的系统发育分析发现，FimH 序列高度保守。然而，我们调查了来自长期留置导管患者的肺炎克雷伯菌分离株，并确定了具有松弛的高结合力 FimH 变体的分离株，这增加了肺炎克雷伯菌在膀胱感染模型中的适应性，表明长期居住在尿路内可能会选择更高结合力的 FimH 变体。