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Extreme resistance to the novel siderophore-cephalosporin cefiderocol in an extensively drug-resistant Klebsiella pneumoniae strain causing fatal pneumonia with sepsis: genomic analysis and synergistic combinations for resistance reversal

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Abstract

Cefiderocol (CFDC) is the first-in-class siderophore-cephalosporin. Klebsiella pneumoniae strain that is extremely resistant to CFDC (MIC: 256 µg/ml) was isolated for the first time in the United Arab Emirates from a patient with pneumonia and sepsis. It belonged to sequence-type 14 (ST14), with a novel core genome ST. Resistance was driven by the co-expression of β-lactamases (blaNDM-1, blaOXA-232 and blaCTX-M-15) and a mutation in catecholate-siderophore receptor, utilized by CFDC to enter the bacterial cell. Synergistic combinations (β-lactamase inhibitors, aztreonam plus CFDC) re-sensitized the bacteria to CFDC. Although CFDC resistance is multifactorial, the combination with β-lactamase inhibitors represents a promising approach in resistance reversal for fighting superbugs.

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Data availability

The assembled genome and plasmid sequences were submitted to the GenBank database under BioProject: PRJNA953676 (bio sample: SAMN34122257) with accession number CP122381 for the chromosome and accession numbers CP122382-CP122388 for the plasmids. Data is available at https://www.ncbi.nlm.nih.gov/bioproject/PRJNA953676.

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Funding

This research was supported by grants from the United Arab Emirates University, UAE (G00004202 and G00003430) awarded to F.A.

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Authors and Affiliations

  1. Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

    Land Daoud, Akela Ghazawi & Farah Al-Marzooq

  2. Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

    Mushal Allam

  3. Tawam Hospital, Al Ain, United Arab Emirates

    Timothy Collyns & Aqeel Saleem

Authors
  1. Land Daoud
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  2. Mushal Allam
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  3. Timothy Collyns
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  4. Akela Ghazawi
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  5. Aqeel Saleem
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  6. Farah Al-Marzooq
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Contributions

Conceptualization: F.A., L.D., and M.A.; methodology: L.D., F.A., M.A., T.C., A.G. and A.S.; formal analysis and investigation: F.A., L.D., M.A., and T.C.; writing—original draft preparation: F.A. and L.D.; writing—review and editing: F.A., L.A., M.A., and T.C.; supervision: F.A.; funding acquisition: F.A.

Corresponding author

Correspondence to Farah Al-Marzooq.

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Ethics approval and consent to participate

Approval to conduct the study was received from Tawam Human Research Ethics Committee, Al-Ain, UAE (approval number: MF2058-2021–761).

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The authors declare no competing interests.

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Daoud, L., Allam, M., Collyns, T. et al. Extreme resistance to the novel siderophore-cephalosporin cefiderocol in an extensively drug-resistant Klebsiella pneumoniae strain causing fatal pneumonia with sepsis: genomic analysis and synergistic combinations for resistance reversal. Eur J Clin Microbiol Infect Dis 42, 1395–1400 (2023). https://doi.org/10.1007/s10096-023-04671-0

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