Characterization of cefiderocol resistant spontaneous mutant variants of Klebsiella pneumoniae producing NDM-5 with single mutation in cirA

Cefiderocol (CFDC) is a siderophore-cephalosporin antibiotic designed to combat highly resistant Gram-negative bacterial infections. Its mechanism involves a strong affinity for iron and active transport into bacterial cells, providing an alternative against strains resistant to common antibiotics. However, the emergence of CFDC resistance in Klebsiella is a growing concern. Recent reports highlight increasing CFDC resistance in K. pneumoniae, particularly associated with mutations in the cirA gene, responsible for encoding a siderophore receptor. Co-localization of blaNDM-like gene and cirA mutations correlates with higher CFDC resistance. The study focuses on a carbapenem-resistant K. pneumoniae strain (Kp-1) with carbapenemases blaNDM-5 and blaOXA-181, recovered from a post-surgery patient. The strain exhibited resistance to all tested antibiotics but susceptibility to CFDC. Heteroresistant populations with the halo on inhibition of CFDC were observed. Genomic analysis identified a novel mutation (W123*) in the cirA gene associated with CFDC resistance. Additionally, increased blaNDM-5 expression in Kp-1 IHC (intra-halo colony) compared to Kp-1 was noted. The coexistence of blaNDM-like and cirA variants, along with high blaNDM-5 expression, explains the observed 21-fold increase in Minimum Inhibition Concentration (MIC) in Kp-1 IHC. The study contributes to understanding the molecular mechanisms driving the emergence of cefiderocol resistance, emphasizing the significance of coexisting mutations in cirA and blaNDM-like genes.