Vol.73 No.S-1 April 2025
Mechanism of action of the novel antibacterial agent cefiderocol against Gram-negative bacteria
1)Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., 3-1-1 Futaba, Toyonaka, Osaka, Japan
Abstract
The key mechanisms of carbapenem resistance in Gram-negative bacteria include hydrolysis by β-lactamases, efflux by drug efflux pumps, and decreased permeability due to deficiency or mutations in the cell membrane porin channels. The activity of antimicrobial agents against carbapenem-resistant bacteria relies heavily on the combination of these resistance mechanisms. Combination therapies with β-lactam/β-lactamase inhibitor have been approved for the treatment of carbapenem-resistant Enterobacterales infections, but the currently available β-lactamase inhibitors may have limited activity against metallo-β-lactamases. Similar to other β-lactam antibacterials, cefiderocol inhibits mainly PBP3 to prevent cell wall synthesis in Gram-negative bacteria. Its structural feature also provides stability against all Ambler class β-lactamases, including metallo-β-lactamases. Furthermore, cefiderocol has a unique mechanism to utilize bacterial iron transport channels by forming a complex with iron ions. Consequently, it retains its effectiveness even in strains with reduced permeability due to deficiency or mutations in porin channels, or in strains that excessively produce drug efflux pumps. Appropriate use of cefiderocol may play a crucial role in combating drug resistance in the future.
Key word
cefiderocol, Gram-negative bacteria, antimicrobial resistance, β-lactamase
Received
November 5, 2024
Accepted
December 10, 2024
Jpn. J. Chemother. 73 (S-1): 1-7, 2025
