Table 2.

Previously Identified Mutations Potentially Contributing to Elevated Minimum Inhibitory Concentrations to Cefiderocol and Other Siderophore-Conjugated Antibiotic Candidates Against Pseudomonas aeruginosa and Acinetobacter baumannii Complex

Target	Organism(s)	Function	Description of Findings
piuA	P. aeruginosa, A. baumannii	Encodes TonB-dependent receptor	Overexpression of piuA increased susceptibility to siderophore-conjugated antibiotics BAL30072 and MC-1 by 4- to 32-fold for P. aeruginosa [5]; transposon insertion in the iron transport receptor piuA increased cefiderocol MICs to P. aeruginosa but did not lead to frank resistance [6]; deletion of piuA in A. baumannii resulted in a 4- to 8-fold decrease in susceptibility to siderophore-conjugated antibiotics BAL30072 and MC-1 [5]; insertions, deletions, and frameshift mutations in the piuA gene in P. aeruginosa isolates led to increased MICs for the siderophore-conjugated antibiotic SMC-3176 [21]; piuA deleted mutants had a 8- to 32-fold reduction in cefiderocol MICs [4]
piuC	P. aeruginosa	Encodes iron-dependent oxygenase and located adjacent to piuA	Frameshift mutation in piuC led to premature termination of translation of the PiuC protein and impacted the adjacent gene piuA, causing a reduction in expression of PiuA [22]; downregulation of the piuC gene increased MICs for siderophore-conjugated antibiotic BAL30072 8- to 16-fold [23]; insertions, deletions, and frameshift mutations in the piuC gene led to increased MICs for the siderophore-conjugated antibiotic SMC-3176 in P. aeruginosa [21]
piuD	P. aeruginosa	Encodes TonB-dependent receptor	Deletion of piuD increased cefiderocol MICs by 32-fold [4]; clinical isolate with no prior exposure to cefiderocol demonstrated resistance potentially associated with mutation in piuD (deletion of an A nucleotide with premature stop codon at amino acid 89) [11]
pirA	P. aeruginosa; A. baumannii	Encodes TonB-dependent receptor	Overexpression of piuA increased susceptibility to siderophore-conjugated antibiotics BAL30072 and MC-1 by 4- to 32-fold [5]; deletion of pirA in A. baumannii resulted in 4- to 8-fold decreased susceptibility to siderophore-conjugated antibiotics BAL30072 and MC-1 [5]; deletion of pirA led to a 2-fold increase in cefiderocol MICs [4]; pirA mutants had a 2-fold reduction in siderophore-conjugated antibiotics BAL30072 and MC-1 [4]; reduced expression of the siderophone receptor gene pirA, possibly in combination with piuA, was associated with cefiderocol resistance in A. baumannii isolates [31]
pirR	P. aeruginosa	Encodes the response regulator of a 2-component regulatory system predicted to activate expression of piuA	Frameshift mutations in pirR increase MICs to SMC-3176, a siderophore-conjugated antibiotic [21]; clinical isolate with no prior exposure to cefiderocol demonstrated resistance potentially associated with mutation in pirR (insertion of a G nucleotide with premature stop codon at amino acid 201) [11]
pvdS	P. aeruginosa	Required for pyoveridine production; mutations in pvdS lead to derepression of pyoveridine synthesis, which enhances production of the pyoveridine siderophore receptor FpvA	Mutation in promotor region of pvdS increased MICs for cefiderocol and the siderophore-conjugated antibiotic SMC-3176 [7, 8, 21]
fecI	P. aeruginosa	Regulator of the synthesis of the iron transporter FecA, contributing to the transport of iron citrate	Single nucleotide change in fecI promotor increased MICs to siderophore-conjugated antibiotic BAL30072 8- to 16-fold [23];. Point mutations in the fecI promoter reduced activity of the siderophore-conjugated antibiotic SMC-3176 against P. aeruginosa [21]; mutations in the promotor region of fecI increased cefiderocol [7]
exbD3	A. baumannii	Component of inner membrane protein complex providing energy to TonB-dependent transporters	Frameshift mutations in exbD3 increased the MICs of siderophore-conjugated antibiotics BAL30072 and MC-1 [5]
tonB	A. baumannii	Component of inner membrane protein complex providing energy to TonB-dependent transporters	Frameshift mutations in tonB3 increased the MICs of siderophore-conjugated antibiotics BAL30072 and MC-1 [5]
ampC	P. aeruginosa	Chromosomal β-lactamase gene	Substitution of leucine for phenylalanine at Ambler amino acid position 147 in the AmpC β-lactamase enzyme, potentially increased cefiderocol MICs [11]
PBP3	A. baumannii	Target site of activity for cefiderocol	A Isoleucine-to-asparagine substitution at position 236 and a histamine-to-tyrosine substitution at position 370 identified in a cefiderocol-resistant isolate. [31]

Abbreviation: MIC, minimum inhibitory concentration.