Molecular mechanisms and clonal distribution of cefiderocol-resistant blaNDM-carrying Escherichia coli: A multi-centre study in China.

BACKGROUND

Reports on cefiderocol resistance are increasing globally despite its unavailability in China. The blaNDM-carrying Escherichia coli was one of the most frequent pathogens mediating cefiderocol resistance.

OBJECTIVE

More systematic resistance mechanisms and potential resistance distribution in the NDM-producing E. coli strains isolated in China require further investigation.

METHODS

We detected the cefiderocol susceptibility of 1,079 common Gram-negative bacteria collected nationwide. Of these, 95 blaNDM-carrying E. coli strains were selected for further study. A series of experiments and bioinformatics analysis were performed to study the resistance mechanisms and the epidemiological distribution of blaNDM-carrying E. coli.

RESULTS

Cefiderocol exhibited potent antibacterial activity against most strains (susceptibility rates were all > 75%) except for blaNDM-carrying E. coli with resistance rate as high as 50.5% (48/95). High-level cefiderocol resistance was attributed to the synergies of multiple mechanisms (blaNDM production and CirA-frameshift mutation/PBP3 insertion). Growth curve showed CirA/PBP3 mutants imposed no additional fitness cost. Among these strains, a total of 20 homologous strains were found, suggesting possible clonal transmission and hospital outbreak. Further study on the blaNDM-carrying E. coli isolated in China during 2021-2024 combined with NCBI database showed that resistance related CirA/PBP3 mutations (CirA-frameshift mutations/I547F and PBP3-Q227H, YRIN333ins, E349K, I532L) were usually co-occurring and concentrated in certain lineages. The diverse source suggested the potential humans-animals-environment spread of resistant strains. Furthermore, the genetic distribution of these potential resistant isolates was associated with their geographical origins.

CONCLUSION

Our study revealed high cefiderocol resistance rates among blaNDM-carrying E. coli isolates in China. More importantly, the molecular mechanisms and potential dissemination of cefiderocol-resistant blaNDM-carrying E. coli were determined to underline the urgency for the 'One Health' strategy and provide a reference for its future use in China.