The emergence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) is a growing concern due to its high mortality and limited treatment options. Although hypermucoviscosity is crucial for CR-hvKp infection, the role of changes in bacterial mucoviscosity in the host colonization and persistence of CR-hvKp is not clearly defined. Herein, we observed a phenotypic switch of CR-hvKp from a hypermucoviscous to a hypomucoviscous state in a patient with scrotal abscess and urinary tract infection (UTI). This switch was attributed to decreased expression of rmpADC , the regulator of mucoid phenotype, caused by deletion of the upstream insertion sequence IS Kpn26 . Postswitching, the hypomucoid variant showed a 9.0-fold decrease in mice sepsis mortality, a >170.0-fold reduction in the ability to evade macrophage phagocytosis in vitro, and an 11.2- to 40.9-fold drop in growth rate in normal mouse serum. Conversely, it exhibited an increased residence time in the mouse urinary tract (21 vs. 6 d), as well as a 216.4-fold boost in adhesion to bladder epithelial cells and a 48.7% enhancement in biofilm production. Notably, the CR-hvKp mucoid switch was reproduced in an antibiotic-free mouse UTI model. The in vivo generation of hypomucoid variants was primarily associated with defective or low expression of rmpADC or capsule synthesis gene wcaJ , mediated by IS Kpn26 insertion/deletion or base-pair insertion. The spontaneous hypomucoid variants also outcompeted hypermucoid bacteria in the mouse urinary tract. Collectively, the IS Kpn26 -associated mucoid switch in CR-hvKp signifies the antibiotic-independent host adaptive evolution, providing insights into the role of mucoid switch in the persistence of CR-hvKp.

中文翻译：

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单个患者尿道中耐碳青霉烯类高毒力肺炎克雷伯菌的适应性进化


耐碳青霉烯类高毒力肺炎克雷伯菌 (CR-hvKp) 的出现因其高死亡率和有限的治疗选择而日益受到关注。尽管高粘膜粘度对于 CR-hvKp 感染至关重要，但细菌粘膜粘度的变化在宿主定植和 CR-hvKp 持续存在中的作用尚不清楚。在此，我们在患有阴囊脓肿和尿路感染（UTI）的患者中观察到 CR-hvKp 从高粘膜粘性状态到低粘膜粘性状态的表型转变。这种转变归因于上游插入序列 IS Kpn26 的删除导致 rmpADC（粘液表型调节剂）的表达减少。转换后，低粘液变体显示小鼠败血症死亡率降低了 9.0 倍，体外逃避巨噬细胞吞噬作用的能力降低了 >170.0 倍，正常小鼠血清中的生长速度降低了 11.2 至 40.9 倍。相反，它在小鼠泌尿道中的停留时间延长（21 天 vs. 6 天），对膀胱上皮细胞的粘附力增加 216.4 倍，生物膜生成增加 48.7%。值得注意的是，CR-hvKp 粘液开关在无抗生素的小鼠 UTI 模型中得到了复制。体内低粘液变体的产生主要与 rmpADC 或荚膜合成基因 wcaJ 的缺陷或低表达有关，由 IS Kpn26 插入/删除或碱基对插入介导。自发的低粘液变体也在小鼠泌尿道中击败了高粘液细菌。总的来说，CR-hvKp 中 IS Kpn26 相关的粘液开关标志着不依赖于抗生素的宿主适应性进化，为了解粘液开关在 CR-hvKp 持久性中的作用提供了见解。