Global molecular epidemiology of the incomplete CirA protein related to cefiderocol resistance in <i>Klebsiella pneumoniae</i> : a genome-based study

CirA is an iron transporter comprising 657 amino acids in <i>Klebsiella pneumoniae,</i> and incomplete CirA alone leads to reduced susceptibility to cefiderocol. We performed a genome-based analysis to study the prevalence of incomplete CirA in <i>K. pneumoniae</i> through analyzing all genomes of this species (<i>n</i> = 55,517, as of 26 October 2023) available in NCBI. We detected incomplete CirA in 633 (1.27%) genomes with the corresponding strains collected since 1911, across 44 countries on six continents, and mostly (<i>n</i> = 563, 88.94%) from humans. Notably, 77 (12.16%) genomes had incomplete CirA in combination with β-lactamases (NDM-1, NDM-5, NDM-7, or KPC-3 plus SHV-11) known to confer cefiderocol resistance. We identified 189 variants of incomplete CirA, including two particularly common ones, a 362-amino-acid remnant due to frameshift by a deletion at <i>cirA</i> nucleotide position 1,083 (116/633, 18.33%) and a 562-amino-acid remnant due to premature stop resulting from a mutation at nucleotide position 1,684 (71/633, 11.22%). The 362-amino-acid remnant was mainly found in ST26 (39/116), ST34 (36/116), and ST359 (31/116) strains. The 562-amino-acid remnant was almost exclusive to ST86 (69/71), particularly related to the hypervirulent capsule type K2. Clonal outbreaks (ST26 in USA, ST34 in UK, and ST86 in Vietnam) and cross-border transmission (ST34 in UK and Portugal) were observed. However, this study has limitations, as the analyzed publicly available <i>K. pneumoniae</i> assemblies are biased, and only mutations resulting in incomplete CirA were considered. In conclusion, <i>K. pneumoniae</i> with incomplete CirA is a global concern, highlighting the urgent need for heightened vigilance and further studies.IMPORTANCECefiderocol is a critically important antimicrobial agent against multidrug-resistant organisms including carbapenem-resistant <i>Klebsiella pneumoniae</i>. We performed a genome-mining study and found incomplete CirA (an iron transporter), which is related to cefiderocol resistance, in a small proportion (1.27%) of publicly available <i>K. pneumoniae</i> genomes. However, <i>K. pneumoniae</i> strains with incomplete CirA are globally distributed and have been present for over a century, well before the clinical use of cefiderocol. One hundred eighty-nine incomplete CirA variants were identified, suggesting multifactorial causes. Almost all publicly available genomes of ST26, ST34, and ST86 <i>K. pneumoniae</i> strains with incomplete CirA have a wide geographic distribution, pointing to the potential existence of particular lineages prone to develop resistance to cefiderocol. Clonal outbreaks and cross-border transmission of strains with incomplete CirA were detected. Incomplete CirA was associated with the hypervirulent K2-ST86 lineage or high-risk multidrug resistance ST16 clone, posing an increased threat or challenge to treatment and infection control.