In Vitro Evolution of Cefiderocol Resistance in an NDM-Producing Klebsiella pneumoniae Due to Functional Loss of CirA

Abstract

Cefiderocol, a newly approved cephalosporin agent with an extensive spectrum of activity against Gram-negative bacteria, binds siderophore and uses its receptors to access the bacterial periplasm. Loss of functional CirA, an iron transporter, has been associated with cefiderocol resistance. By serially exposing an NDM-producing Klebsiella pneumoniae clinical strain to cefiderocol, we obtained a mutant with cefiderocol MIC of >128 μg/ml. The mutant contained an early stop codon in the iron transporter gene cirA , and its complementation fully restored susceptibility. The cirA -deficient mutant was competed out by the parental strain in vitro , suggesting reduced fitness. IMPORTANCE Cefiderocol, a newly approved cephalosporin agent with an extensive spectrum of activity against Gram-negative bacteria, is a siderophore cephalosporin that utilizes iron transporters to access the bacterial periplasm. Loss of functional CirA, an iron transporter, has been associated with cefiderocol resistance. Here, we show that such genetic change can be selected under selective pressure and cause high-level cefiderocol resistance, but with a high fitness cost. Whether these resistant mutants can survive beyond selective pressure will inform stewardship of this agent in the clinic.