Table 1.
Previously Identified Mutations Contributing to Elevated Minimum Inhibitory Concentrations in the Enterobacterales to Cefiderocol and Other Siderophore-Conjugated Antibiotic Candidates
| Target | Organism(s) | Function | Description of findings |
|---|---|---|---|
| tonB | Escherichia coli | Component of inner membrane protein complex providing energy to TonB-dependent transporters | tonB mutants had significantly decreased susceptibility to the siderophore-conjugated antibiotics KP-736,16 BMS-180680,11 E-0702,17 pirazmonam,15 and U-78,60815 |
| cirA | E. coli, Enterobacter cloacae | Encodes receptor which preferentially transports catecholate siderophores | Double knockout of both cirA and fiu resulted in a 16-fold increase in cefiderocol MICs12; double mutants of cirA and fiu had decreased susceptibility to the siderophore-conjugated antibiotics KP-736,16 BMS-180680,11 pirazmonam,15 and U-78,60815; heterogeneous mutations in the cirA gene conferred resistance to cefiderocol13 |
| fiu | E. coli | Encodes receptor that preferentially transports catecholate siderophores | Double knockout of both cirA and fiu resulted in a 16-fold increase in cefiderocol MICs12; double mutants of cirA and fiu had decreased susceptibility to the siderophore-conjugated antibiotics KP-736,16 BMS-180680,11 pirazmonam,15 and U-78,60815 |
| baeS | Klebsiella pneumoniae | Encodes a sensor kinase protein of the two-component BaeSR signal transduction system reported to affect a variety of envelope stress response pathways. | Mutations in baeS increased cefiderocol MICs 32-fold.14 Val295Gly, Thr279Pro and Thr200Pro associated with elevated cefiderocol MICs in mutants44 |
| exbD | K. pneumoniae | TonB-dependent energy transduction system reported to affect the function of iron transporters | A Leu49frame shift mutation led to elevated cefiderocol MICs44 |
| envZ | K. pneumoniae | Two-component transcriptional regulator reported to affect the expression of iron transporters | Val124Gly, Val147Gly, Ile152Asp, Leu18frame shift and Val54Gly mutations led to elevated cefiderocol MICs in mutants44 |
| ompR | K. pneumoniae | Two-component transcriptional regulator reported to affect the expression of iron transporters | Met62Arg mutation led to elevated cefiderocol MICs in mutants44 |
| yicM | K. pneumoniae | Unknown function | Mutations in Gly32ASP in two separate mutants led to elevated cefiderocol MICs44 |
| ampC | E. cloacae complex | Chromosomal β-lactamase gene | Two amino acid deletion in the R2 loop of AmpC beta-lactamase (i.e., alanine and leucine at positions 292 and 293, respectively) led to resistance to cefiderocol in two separate clinical E. hormaechei isolates19; alanine-proline deletion at positions 294 and 295 and leucine-to-valine substitution in position 296 increased cefiderocol MICs in an E. cloacae complex isolate18 |
| bla NDM | K. pneumoniae and E. cloacae | Carbapenemase enzyme | Resistance among E. cloacae and K. pneumoniae associated with the metallo-β-lactamase, NDM. When testing these isolates in combination with the beta-lactamase inhibitor dipicolonic acid, the cefiderocol MICs decreased5 |
MIC, minimum inhibitory concentration; NDM, New Delhi metallo-β-lactamase.