Journal Article

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

Cabanel, Nicolas, Patiño-Navarrete, Rafael, Gauthier, Lauraine, Rosinski-Chupin, Isabelle, Glaser, Philippe, Naas, Thierry, Madec, Jean-Yves, Hamze, Monzer, Bonnin, Remy A., Takissian, Julie

2020

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Alleles / Analysis / Anopheles / Antibiotic resistance / Antibiotics / Bacterial evolution / Bacterial genetics / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / beta-Lactam Resistance / beta-Lactamases - genetics / beta-Lactamases - metabolism / Binding proteins / Biochemistry, Molecular Biology / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carbapenemase / Carbapenems / Drug resistance / E coli / Enteropathogenic Escherichia coli - classification / Enteropathogenic Escherichia coli - drug effects / Enteropathogenic Escherichia coli - genetics / Epics / Epidemiology / Escherichia coli / Escherichia coli Proteins - genetics / Evolution, Molecular / Evolutionary genetics / Gene Transfer, Horizontal / Genes / Genetic engineering / Genomes / Genomics / Human Genetics / Lactams / Lateral gene transfers / Life Sciences / Medicine/Public Health / Metabolomics / Microbial drug resistance / Molecular biology / Multidrug resistance / Multidrug resistant organisms / Mutation / Nucleotide sequence / Oxalic acid / Pandemics / Pathogenic microorganisms / Penicillin / Penicillin-binding protein / Penicillin-binding protein 3 / Penicillin-binding proteins / Penicillin-Binding Proteins - genetics / Penicillins / Peptidoglycan Glycosyltransferase - genetics / Permeability / Phylogenetics / Phylogeny / Porin / Porins - genetics / Protein binding / Proteins / Public health / Public health movements / Recombination / Systems Biology / β-Lactam antibiotics