Abstract

Background Reports on cefiderocol resistance are increasing globally despite its unavailability in China. The bla NDM -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 bla NDM -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 bla NDM -carrying E. coli . Results Cefiderocol exhibited potent antibacterial activity against most strains (susceptibility rates were all > 75%) except for bla NDM -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 ( bla NDM 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 bla NDM -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 bla NDM -carrying E. coli isolates in China. More importantly, the molec