Cefiderocol is a siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. It has in vitro activity against the non-fermenting Gram-negative bacteria causing urinary tract infections. It is a siderophore conjugate molecule, which means it's a single molecular structure with two distinct roles: a siderophore and a cephalosporin. Specifically, it combines a catechol-type siderophore and cephalosporin core with side chains similar to cefepime and ceftazidime. The cephalosporin moiety is the active antimicrobial component. Cefiderocol was developed by Shionogi & Co., Ltd. and was formerly called S-649266.
Cefiderocol is freely soluble in DMSO.
| Mechanism of Action | Cefiderocol binds to iron and enters the bacterial cell using the bacteria's own iron transport system to evade the bacterial porin channels, likened to the 'Trojan horse' and can allow it access into the periplasmic space. Bacteria naturally secrete siderophores to scavenge iron from the human host, which they need for growth, replication, and metabolism. Once in the periplasmic space, the iron atom disassociates from the siderophore and crosses the cytoplasmic membrane into the cytoplasm, leaving Cefiderocol in the periplasmic space, where it can apply its antimicrobial effects. It binds to and inhibits penicillin-binding proteins (PBPs), primarily BBP3, preventing cell wall synthesis and ultimately causing death of the bacterial cell. |
| Spectrum |
The spectrum of activity of Cefiderocol differs from most other beta-lactam agents. It has activity against Gram-negative bacilli including multi-drug-resistant (MDR) Gram-negative bacteria, including carbapenem-resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. It does not have activity against Gram-positive or anaerobic organisms. Siderophore antibiotics are effective against an array of extended-spectrum beta-lactamases (ESBL)s. They can also enter cells via passive diffusion through porin channels and is stable against all known classes of β-lactamases. |
| Microbiology Applications |
Cefiderocol (S-649266), a novel siderophore cephalosporin conjugated with a catechol moiety, has a characteristic antibacterial spectrum with a potent activity against a broad range of aerobic Gram-negative bacterial species, including carbapenem-resistant strains of Enterobacteriaceae and nonfermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol has affinity mainly for penicillin-binding protein 3 (PBP3) of Enterobacteriaceae and nonfermenting bacteria similar to that of Ceftazidime. Heteroresistance is a form of antibiotic resistance where an isolate harbors a minority resistant cell subpopulation that can coexist with a majority susceptible population and is many times undetected by standard antimicrobial susceptibility testing (AST). Cefiderocol heteroresistance among carbapenem-resistant bacteria that were collected in the Georgia Emerging Infections Program (GA, US) (Chob et al, 2021). Heteroresistance was observed in a representative carbapenem-resistant A. baumannii isolate. Multiple mechanisms of mutation-derived resistance have been reported, which include mutations in genes associated with a) siderophore regulation and synthesis; b) iron uptake c) two-component regulatory systems, and d) penicillin-binding proteins. (Zhanel et al, 2019). Iron concentrations need to be considered when doing in vitro antimicrobial susceptibility testing. Broth microdilution (BMD) and disk diffusion methods have been developed. For BMD, cation-adjusted Mueller-Hinton broth (CAMHB) requires iron depletion to provide MICs predictive of in vivo activity. A method to prepare iron-depleted CAMHB (ie ID-CAMHB) has been described by CLSI. For disk diffusion, standard Mueller-Hinton agar is used, presumably because iron is bound in the medium. |
| Molecular Formula | C30H34ClN7O10S2 |
| References |
Aoki et al (2018) Cefiderocol (S-649266), A new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other Gram-negative pathogens including multi-drug resistant bacteria: Structure activity relationship. Eur. J. Med. Chem. 155:847-868. PMID 29960205 Chob JE, Ozturk T, Satola SW, Jacob JT and Weiss DS (2021) Widespread Cefiderocol hetroresistance in carbapenem-resistant Gram-negative pathogens. Lancet 21(5):P597-598 Ito A et al (2017) In vitro antibacterial properties of Cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria. Antimicrob. Agents Chemother. 62(1). pii: e01454-17 PMID 29061741 Jean SS, Hsueh SC, Lee WS, Hsueh PR (2019) Cefiderocol: A promising antibiotic against multidrug-resistant Gram-negative bacteria. Expert Rev. Anti.Infect.Ther.17(5):307-309 PMID 31055983 Katsube T et al (2017) Cefiderocol, a siderophore cephalosporin for Gram-negative bacterial infections: Pharmacokinetics and safety in subjects with renal impairment. J. Clin. Pharmacol. 57(5):584-591 PMID 27874971 Tillotson GS (2016) Trojan horse antibiotics- A novel way to circumvent Gram-negative bacterial resistance? Infect. Dis. (Auckl). 9:45-52 PMID 27773991 Zhanel GG et al (2019) Cefiderocol: A siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs 79:271–289 |