Among the most urgent public health threats is the worldwide emergence of carbapenem-resistant Enterobacteriaceae1-4, which are resistant to the antibiotic class of 'last resort'. In the United States and Europe, carbapenem-resistant strains of the Klebsiella pneumoniae ST258 (ref. 5) sequence type are dominant, endemic6-8 and associated with high mortality6,9,10. We report the global evolution of pathogenicity in carbapenem-resistant K. pneumoniae, resulting in the repeated convergence of virulence and carbapenem resistance in the United States and Europe, dating back to as early as 2009. We demonstrate that K. pneumoniae can enhance its pathogenicity by adopting two opposing infection programs through easily acquired gain- and loss-of-function mutations. Single-nucleotide polymorphisms in the capsule biosynthesis gene wzc lead to hypercapsule production, which confers phagocytosis resistance, enhanced dissemination and increased mortality in animal models. In contrast, mutations disrupting capsule biosynthesis genes impair capsule production, which enhances epithelial cell invasion, in vitro biofilm formation and persistence in urinary tract infections. These two types of capsule mutants have emerged repeatedly and independently in Europe and the United States, with hypercapsule mutants associated with bloodstream infections and capsule-deficient mutants associated with urinary tract infections. In the latter case, drug-tolerant K. pneumoniae can persist to yield potentially untreatable, persistent infection.

中文翻译：

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耐碳青霉烯类肺炎克雷伯菌毒力和持久性的适应性进化。

最紧迫的公共卫生威胁之一是全球出现了耐碳青霉烯类肠杆菌科细菌 1-4，它们对“最后手段”的抗生素类具有耐药性。在美国和欧洲，肺炎克雷伯菌 ST258（参考文献 5）序列类型的碳青霉烯类耐药菌株占优势，是地方性的 6-8 并且与高死亡率相关 6,9,10。我们报道了耐碳青霉烯类肺炎克雷伯菌的全球致病性演变，导致美国和欧洲的毒力和碳青霉烯类耐药性反复趋同，最早可以追溯到 2009 年。我们证明了肺炎克雷伯菌可以增强其致病性通过容易获得的功能获得和功能丧失突变采用两种相反的感染程序。胶囊生物合成基因 wzc 中的单核苷酸多态性导致超胶囊产生，这在动物模型中赋予吞噬作用抗性、增强的传播和增加的死亡率。相反，破坏胶囊生物合成基因的突变会损害胶囊的产生，从而增强上皮细胞的侵袭、体外生物膜的形成和尿路感染的持久性。这两种类型的胶囊突变体在欧洲和美国反复出现，独立出现，超胶囊突变体与血流感染相关，胶囊缺陷突变体与尿路感染相关。在后一种情况下，耐药性肺炎克雷伯菌可以持续产生潜在的无法治疗的持续感染。在动物模型中加强传播和增加死亡率。相反，破坏胶囊生物合成基因的突变会损害胶囊的产生，从而增强上皮细胞的侵袭、体外生物膜的形成和尿路感染的持久性。这两种类型的胶囊突变体在欧洲和美国反复出现，独立出现，超胶囊突变体与血流感染相关，胶囊缺陷突变体与尿路感染相关。在后一种情况下，耐药性肺炎克雷伯菌可以持续产生潜在的无法治疗的持续感染。在动物模型中加强传播和增加死亡率。相反，破坏胶囊生物合成基因的突变会损害胶囊的产生，从而增强上皮细胞的侵袭、体外生物膜的形成和尿路感染的持久性。这两种类型的胶囊突变体在欧洲和美国反复出现，独立出现，超胶囊突变体与血流感染相关，胶囊缺陷突变体与尿路感染相关。在后一种情况下，耐药性肺炎克雷伯菌可以持续产生潜在的无法治疗的持续感染。这两种类型的胶囊突变体在欧洲和美国反复出现，独立出现，超胶囊突变体与血流感染相关，胶囊缺陷突变体与尿路感染相关。在后一种情况下，耐药性肺炎克雷伯菌可以持续产生潜在的无法治疗的持续感染。这两种类型的胶囊突变体在欧洲和美国反复出现，独立出现，超胶囊突变体与血流感染相关，胶囊缺陷突变体与尿路感染相关。在后一种情况下，耐药性肺炎克雷伯菌可以持续产生潜在的无法治疗的持续感染。