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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.

Stepwise evolution and convergent recombination underlie the global dissemination of carbapenemase-producing Escherichia coli