Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa

Abstract

Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the third-position side chain. The in vitro activity of cefiderocol against Pseudomonas aeruginosa was enhanced under iron-depleted conditions, whereas that of ceftazidime was not affected. The monitoring of [thiazole-14C]cefiderocol revealed the increased intracellular accumulation of cefiderocol in P. aeruginosa cells incubated under iron-depleted conditions compared with those incubated under iron-sufficient conditions. Cefiderocol was shown to have potent chelating activity with ferric iron, and extracellular iron was efficiently transported into P. aeruginosa cells in the presence of cefiderocol as well as siderophores, while enhanced transport of extracellular ferric iron was not observed when one of the hydroxyl groups of the catechol moiety of cefiderocol was replaced with a methoxy group. We conclude that cefiderocol forms a chelating complex with iron, which is actively transported into P. aeruginosa cells via iron transporters, resulting in potent antibacterial activity of cefiderocol against P. aeruginosa.

Cefiderocol, a Siderophore Cephalosporin for Gram‐Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment

“…The catechol moiety of cefiderocol contributes to its potent antimicrobial activity against Gram-negative bacteria including those resistant to other antibiotics by functioning as a siderophore, an iron-complexing protein, to form a chelating complex with ferric iron and utilize the bacterial iron transport system to penetrate the outer membrane of the Gram-negative organisms. 11 This concept of carrying compounds into other cells such as bacteria has been likened to the "Trojan horse." 12 Cefiderocol exposure increased in subjects with moderate and severe renal impairment and ESRD compared to those with normal renal function.…”

Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

“…It possesses a unique mechanism for penetrating efficiently into Gram-negative pathogens. It uses a BTrojan horse^strategy by binding free iron and is then actively transported into bacterial cells across the outer membrane of Gram-negative bacteria by way of the iron-transport system [11,12]. Cefiderocol is a cephalosporin molecule with an attached catechol moiety on the 3-position side chain which binds to ferric iron [11].…”

Compassionate Use of Cefiderocol in the Treatment of an Intraabdominal Infection Due to Multidrug‐Resistant Pseudomonas aeruginosa: A Case Report

“…The expanded gram‐negative activity, over that of ceftazidime and cefepime, appears to be due to the addition of a catechol moiety to the side chain at position 3 on the β‐lactam ring. This gives cefiderocol its siderophore properties as it complexes with extracellular iron and facilitates penetration into the periplasmic space by bacterial iron transporters, even in the presence of decreased porin channels or increased efflux pumps . It is also stable against a wide array of β‐lactamases including enzymes from each of the four Ambler classifications .…”