Disruption of cAMP Signalling and RNA Regulation Confers Cefiderocol Resistance in Acinetobacter baumannii
- 1Univeristy of Queensland
Abstract
Cefiderocol is a siderophore-conjugated cephalosporin used to treat severe multidrug-resistant Gram-negative infections. Its recent prioritisation for US national preparedness underscores its clinical importance, yet resistance can emerge despite apparent in vitro susceptibility. Here, we identify two regulatory routes to cefiderocol resistance in carbapenem-resistant Acinetobacter baumannii (CRAB): mutation of the cAMP-producing adenylate cyclase CavA and truncation of the glycine-rich RNA-binding domain of the post-transcriptional regulator Hfq. These variants occurred in contemporary clinical isolates, conferred resistance in a murine CRAB lung-infection model and imposed minimal fitness costs. In Escherichia coli, deletion of the CavA orthologue cyaA increased competitive fitness during sub-inhibitory cefiderocol exposure. Hfq-CLASH and integrated omics revealed Hfq-dependent regulation of Fur-associated iron homeostasis in A. baumannii. Under iron limitation, truncated-Hfq induced a defence-primed state that attenuated siderophore uptake and reduced cefiderocol activity. These findings identify bacterial regulatory state and iron availability as determinants of cefiderocol susceptibility, with implications for resistance surveillance and susceptibility testing.
Related
- IscR-mediated morphological regulation confers virulence and stress resistance by reducing stress molecule uptake in Acinetobacter baumannii
- Cross-resistance to cefiderocol and ceftazidime–avibactam in KPC β-lactamase mutants and the inoculum effect
- Relative inhibitory activities of taniborbactam and xeruborbactam against KPC variants conferring reduced susceptibility or resistance to ceftazidime/avibactam, cefiderocol, and cefepime/taniborbactam
- Genomic and structural insights into the in vivo development of cefiderocol resistance in Klebsiella pneumoniae.
- Second-site capsule-locus mutations, not Ade efflux disruption, determine phage susceptibility across an Acinetobacter baumannii transposon mutant panel
BibTeX
@misc{oliveira2026disruption,
title = {{Disruption of cAMP Signalling and RNA Regulation Confers Cefiderocol Resistance in Acinetobacter baumannii}},
author = {D. M. P. De Oliveira and R. Heaton and H. Whyte and L. Buedenbender and A. Indraratna and N. T. K. Nguyen and M.-D. Phan and S. F. Alquethamy and Y. Hirose and B. Permana and A. Wright and A. Y. Peleg and M. Nochomovitz and P. N. A. Harris and K. A. Ramsay and P. Holmes and M. A. T. Blaskovich and D. L. Paterson and J. D. Boyce and A. Everest-Dass and M. A. Schembri and J. J. Tree and M. J. Walker and B. M. Forde},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.755845},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.755845v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Disruption of cAMP Signalling and RNA Regulation Confers Cefiderocol Resistance in Acinetobacter baumannii
AU - D. M. P. De Oliveira
AU - R. Heaton
AU - H. Whyte
AU - L. Buedenbender
AU - A. Indraratna
AU - N. T. K. Nguyen
AU - M.-D. Phan
AU - S. F. Alquethamy
AU - Y. Hirose
AU - B. Permana
AU - A. Wright
AU - A. Y. Peleg
AU - M. Nochomovitz
AU - P. N. A. Harris
AU - K. A. Ramsay
AU - P. Holmes
AU - M. A. T. Blaskovich
AU - D. L. Paterson
AU - J. D. Boyce
AU - A. Everest-Dass
AU - M. A. Schembri
AU - J. J. Tree
AU - M. J. Walker
AU - B. M. Forde
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.755845
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.755845v1
AB - Cefiderocol is a siderophore-conjugated cephalosporin used to treat severe multidrug-resistant Gram-negative infections. Its recent prioritisation for US national preparedness underscores its clinical importance, yet resistance can emerge despite apparent in vitro susceptibility. Here, we identify two regulatory routes to cefiderocol resistance in carbapenem-resistant Acinetobacter baumannii (CRAB): mutation of the cAMP-producing adenylate cyclase CavA and truncation of the glycine-rich RNA-binding domain of the post-transcriptional regulator Hfq. These variants occurred in contemporary clinical isolates, conferred resistance in a murine CRAB lung-infection model and imposed minimal fitness costs. In Escherichia coli, deletion of the CavA orthologue cyaA increased competitive fitness during sub-inhibitory cefiderocol exposure. Hfq-CLASH and integrated omics revealed Hfq-dependent regulation of Fur-associated iron homeostasis in A. baumannii. Under iron limitation, truncated-Hfq induced a defence-primed state that attenuated siderophore uptake and reduced cefiderocol activity. These findings identify bacterial regulatory state and iron availability as determinants of cefiderocol susceptibility, with implications for resistance surveillance and susceptibility testing.
ER -