IS<i>903B</i>-mediated <i>cirA</i> inactivation confers cefiderocol resistance and adaptive fitness in carbapenem-resistant <i>Klebsiella pneumoniae</i>

Although <i>cirA</i> inactivation is a recognized mechanism of FDC resistance, whether different forms of <i>cirA</i> disruption influence bacterial adaptation and persistence remains unclear. By analyzing 1,965 publicly available long-read genomes and 480 clinical isolates, we found that <i>cirA</i> loss-of-function mutations were rare (1.1%) but accumulated over time among isolates from China, with four independently emerged <i>cirA</i>-inactivated ST11 isolates identified across distinct phylogenetic branches.

Functional characterization of a representative ST11-KL64 clinical isolate showed that IS<i>903B</i>-mediated <i>cirA</i> inactivation conferred high-level FDC resistance (minimum inhibitory concentration, 128 μg/mL), which was reversed by <i>cirA</i> complementation. Functional assays further demonstrated that, unlike complete <i>cirA</i> deletion, IS<i>903B</i>-mediated <i>cirA</i> inactivation enhanced bacterial adaptation under iron-limited conditions, including competitive fitness, plasmid stability, and host-associated survival.