Work

Combinatorial effects of a novel SHV-248 variant, NDM-5, and ompK35 deficiency drive high-level cefiderocol resistance in Klebsiella pneumoniae

Year: 2026

Type: article

Abstract: ABSTRACT Cefiderocol holds significant therapeutic value against metallo-β-lactamase-producing Enterobacterales. However, reduced susceptibility to cefiderocol in NDM-producing strains is increasingly observed. This study elucidated the mechanism of high-level cefiderocol resistance in a clinical Klebsiella pneumoniae strain (KP5663, ST147-KL64) producing NDM-5, which emerged without prior drug exposure. Whole-genome sequencing identified, alongside bla NDM-5 and ompK35 / ompK36 porin deficiencies, a novel β-lactamase gene variant, bla SHV-248 . Functional characterization revealed that SHV-248 exhibited a moderately higher affinity for cefiderocol (binding energy: −5.15 kcal/mol) and a 1.6-fold greater hydrolytic activity against nitrocefin compared to SHV-12. Consistent with this, heterologous expression of bla SHV-248 , but not bla SHV-12 , increased the cefiderocol minimum inhibitory concentration (MIC) by fourfold, although the MIC remained within the susceptible range. Critically, genetic complementation demonstrated that restoring functional ompK35 alone reduced the cefiderocol MIC of KP5663 by 16-fold, whereas complementation with ompK36 had no effect. These findings define a novel synergistic triad wherein the combined, rather than individual, action of bla NDM-5 , the novel variant bla SHV-248 , and porin deficiency (primarily ompK35 ) is necessary and sufficient for high-level cefiderocol resistance. IMPORTANCE This study identifies a novel SHV variant and, more importantly, delineates a distinct “key determinant combination” model for cefiderocol resistance. This model does not rely on exceptional enzyme overproduction but on the convergence of three clinically relevant factors: a transmissible bla NDM-5 , a chromosomally evolving SHV variant with incremental efficiency gains, and frequent porin loss. It underscores that, for NDM-producing Klebsiella pneumoniae , risk assessment must evolve to evaluate porin status alongside β-lactamase profiles, as even modestly more efficient enzymes like SHV-248 can become decisive factors within a permissive genetic background.

Source: Microbiology Spectrum

DOI: 10.1128/spectrum.00026-26