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] |
| 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.
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] |
| 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.
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