BACKGROUND Carbapenem-resistant Enterobacteriaceae are considered by WHO as "critical" priority pathogens for which novel antibiotics are urgently needed. The dissemination of carbapenemase-producing Escherichia coli (CP-Ec) in the community is a major public health concern. However, the global molecular epidemiology of CP-Ec isolates remains largely unknown as well as factors contributing to the acquisition of carbapenemase genes. METHODS We first analyzed the whole-genome sequence and the evolution of the E. coli sequence type (ST) 410 and its disseminated clade expressing the carbapenemase OXA-181. We reconstructed the phylogeny of 19 E. coli ST enriched in CP-Ec and corresponding to a total of 2026 non-redundant isolates. Using the EpiCs software, we determined the significance of the association between specific mutations and the acquisition of a carbapenemase gene and the most probable order of events. The impact of the identified mutations was assessed experimentally by genetic manipulations and phenotypic testing. RESULTS In 13 of the studied STs, acquisition of carbapenemase genes occurred in multidrug-resistant lineages characterized by a combination of mutations in ftsI encoding the penicillin-binding protein 3 and in the porin genes ompC and ompF. Mutated ftsI genes and a specific ompC allele related to that from ST38 inducing reduced susceptibility to diverse β-lactams spread across the species by recombination. We showed that these mutations precede in most cases the acquisition of a carbapenemase gene. The ompC allele from ST38 might have contributed to the selection of CP-Ec disseminated lineages within this ST. On the other hand, in the pandemic ST131 lineage, CP-Ec were not associated with mutations in ompC or ftsI and show no signs of dissemination. CONCLUSIONS Lineages of CP-Ec have started to disseminate globally. However, their selection is a multistep process involving mutations, recombination, acquisition of antibiotic resistance genes, and selection by β-lactams from diverse families. This process did not yet occur in the high-risk lineage ST131.

中文翻译：

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逐步进化和融合重组是产生碳青霉烯酶的大肠杆菌在全球范围内传播的基础。

背景技术耐碳青霉烯的肠杆菌科被WHO认为是“紧急的”优先病原体，迫切需要新的抗生素。产生碳青霉烯酶的大肠杆菌（CP-Ec）在社区中的传播是主要的公共卫生问题。然而，CP-Ec分离物的全球分子流行病学以及导致碳青霉烯酶基因获得的因素仍然未知。方法我们首先分析了全基因组序列和大肠杆菌序列类型（ST）410及其散布进化支，表达碳青霉烯酶OXA-181的进化。我们重建了富含CP-Ec的19种大肠杆菌ST的系统发育，对应于总共2026个非冗余分离株。使用EpiCs软件，我们确定了特定突变与碳青霉烯酶基因和最可能的事件顺序之间的关联的重要性。通过基因操作和表型测试，通过实验评估了鉴定出的突变的影响。结果在13个被研究的ST中，碳青霉烯酶基因的获得发生在多药耐药谱系中，其特征是编码青霉素结合蛋白3的ftsI和孔蛋白基因ompC和ompF发生突变。突变的ftsI基因和一个特定的ompC等位基因，与来自ST38的基因相关，通过重组可降低对散布在整个物种中的各种β-内酰胺的敏感性。我们表明，在大多数情况下，这些突变先于碳青霉烯酶基因的获得。来自ST38的ompC等位基因可能有助于选择该ST中CP-Ec传播的血统。另一方面，在大流行的ST131谱系中，CP-Ec与ompC或ftsI的突变无关，并且没有传播迹象。结论CP-Ec的血统已经开始在全球范围内传播。然而，它们的选择是一个多步骤的过程，涉及突变，重组，抗生素抗性基因的获得，以及来自不同家族的β-内酰胺的选择。高风险沿袭ST131尚未发生此过程。它们的选择是一个多步骤的过程，涉及突变，重组，抗生素抗性基因的获取以及来自不同家族的β-内酰胺的选择。高风险沿袭ST131尚未发生此过程。它们的选择是一个多步骤的过程，涉及突变，重组，抗生素抗性基因的获取以及来自不同家族的β-内酰胺的选择。高风险沿袭ST131尚未发生此过程。