The siderophore moiety of the conjugates sequesters environmental iron, and then the iron–siderophore–antibiotic complex binds to an iron transporter outer membrane protein and is actively taken up. Several pharmaceutical companies have identified siderophore-conjugated antibiotics with potent in vitro antibacterial activity against gram-negative bacteria, including Pseudomonas aeruginosa. īased on these observations, research into synthetic β-lactams conjugated with siderophores was started in the 1980s. Research into sideromycins has revealed that the involvement of an active transport system results in greater susceptibility to antibiotics and lower minimum inhibitory concentrations (MICs) compared with those molecules that are transported through the outer membrane via a passive or other mechanism. Albomycin is taken up by the bacterial cell via an active transport system through the outer membrane, a mechanism that overcomes the problem of poor permeability of the outer membrane of gram-negative bacteria to antibiotics. For example, albomycin is a naturally occurring sideromycin, and contains a ferrichrome siderophore group and a thioribosyl pyrimidine antibiotic. Siderophore molecules may be covalently linked to chemical moieties with antibacterial activity, and are then known as sideromycins. Siderophores are natural iron-chelating molecules that are produced and released by nearly all bacterial species to facilitate the transport of iron into the bacterial cell for survival and growth. This article reviews the discovery and chemistry of cefiderocol, as well as some of the key microbiological and in vivo findings on cefiderocol from recently conducted investigations.Ĭarbapenemase, cephalosporin, gram-negative bacteria, penicillin-binding protein 3, siderophore Cefiderocol has demonstrated promising in vitro antibacterial and bactericidal activity, which correlates with its in vivo efficacy in several animal models. Furthermore, cefiderocol has demonstrated structural stability against hydrolysis by both serine- and metallo-β-lactamases, including clinically relevant carbapenemases such as Klebsiella pneumoniae carbapenemase, oxacillin carbapenemase-48, and New Delhi metallo-β-lactamase.
Following the chelation of iron, cefiderocol is actively transported across the outer membrane of the bacterial cell to the periplasmic space via specialized iron transporter channels. The unique chemical component is the addition of a catechol moiety on the C-3 side chain, which chelates iron and mimics naturally occurring siderophore molecules.
The structural characteristics of cefiderocol show similarity to both ceftazidime and cefepime, which enable cefiderocol to withstand hydrolysis by β-lactamases. Cefiderocol is a novel siderophore cephalosporin targeting gram-negative bacteria, including strains with carbapenem resistance. The emergence of antimicrobial resistance is a significant public health issue worldwide, particularly for healthcare-associated infections caused by carbapenem-resistant gram-negative pathogens.