2026-10-14T06:10:50Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33997551 2026-09-25T16:52:19Z category_7 category_8 category_13 category_21 category_24 category_272 category_39 category_64 category_128 category_132 category_134 portal_87 item_type_3 month_year_09_2026

IS903B-mediated cirA inactivation confers cefiderocol resistance and adaptive fitness in carbapenem-resistant Klebsiella pneumoniae Yuxuan Liu (349237) Xinyue Dai (738111) Hanxu Hong (24563139) Chuwen Zhao (18439627) Yun Cao (111731) Linping Fan (24823343) Yang Liu (4829) Medicine Microbiology Genetics Biotechnology Evolutionary Biology Environmental Sciences not elsewhere classified Ecology Cancer Hematology Infectious Diseases Virology Klebsiella pneumoniae cefiderocol resistance cirA IS903B iron-limited adaptation Cefiderocol (FDC) is a last-resort antimicrobial for the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP). Although cirA inactivation is a recognized mechanism of FDC resistance, whether different forms of cirA disruption influence bacterial adaptation and persistence remains unclear. By analyzing 1,965 publicly available long-read genomes and 480 clinical isolates, we found that cirA loss-of-function mutations were rare (1.1%) but accumulated over time among isolates from China, with four independently emerged cirA-inactivated ST11 isolates identified across distinct phylogenetic branches. Functional characterization of a representative ST11-KL64 clinical isolate showed that IS903B-mediated cirA inactivation conferred high-level FDC resistance (minimum inhibitory concentration, 128 μg/mL), which was reversed by cirA complementation. Functional assays further demonstrated that, unlike complete cirA deletion, IS903B-mediated cirA inactivation enhanced bacterial adaptation under iron-limited conditions, including competitive fitness, plasmid stability, and host-associated survival. Transcriptomic, enzymatic, and genetic analyses supported distinct Fe-S-associated metabolic remodelling in cirA::IS903B, while deletion of sufS attenuated these adaptive phenotypes. Construction of cirA::IS903B derivatives in multiple independent ST11 clinical isolates reproduced these adaptive phenotypes across diverse genetic backgrounds. Together, these findings demonstrate that IS903B-mediated cirA inactivation not only confers high-level FDC resistance but also promotes bacterial adaptation through mechanisms distinct from complete cirA deletion. The combination of resistance, enhanced adaptation, and increased plasmid stability suggests that specific resistance-associated cirA mutations may facilitate the persistence and dissemination of high-risk CRKP clones. Monitoring cirA integrity and IS insertion status may help identify FDC-resistant lineages with increased dissemination potential. 2026-09-25T16:52:19Z Dataset Dataset 10.6084/m9.figshare.33997551.v1 https://figshare.com/articles/dataset/IS_i_903B_i_-mediated_i_cirA_i_inactivation_confers_cefiderocol_resistance_and_adaptive_fitness_in_carbapenem-resistant_i_Klebsiella_pneumoniae_i_/33997551 CC BY 4.0