Mechanism of action of cefiderocol

Abstract

Gram-negative bacilli are intrinsically resistant to many antibiotics due to the low permeability of their outer membra-ne. The most effective strategy to solve this problem has been the design of antibiotics that cross the membrane using speci-fic transport systems. This is the case of cefiderocol, which, un-like cefepime or ceftazidime, has a chlorocatechol group at the end of the C-3 side chain. This group is recognized by transporters located in the outer membrane that allow cefiderocol to accumulate in the periplasmic space. Furthermore, cefidero-col is not a substrate for efflux pumps and the configuration of the side chains at C-7 and in particular at C-3 confer it a high stability against hydrolysis by most beta-lactamases of clinical interest including class A (KPC, BLEEs), C (ampC) or D (OXA-48) serine beta-lactamases and metallo-betalactamases (NDM, VIM. IMP). In order to better understand the mechanism of action of cefiderocol, the importance of iron in bacterial metabolism and the competition for iron between bacteria and host are reviewed.