Cited by 357Antibiotic Resistance in BacteriaBacterial Genetics and BiotechnologyAntibiotics Pharmacokinetics and Efficacy

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

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Ito, Akinobu, Nishikawa, Toru, Matsumoto, Shuhei, Yoshizawa, Hidenori, Sato, Takafumi, Nakamura, Rio, Tsuji, Masakatsu, Yamano, Yoshinori·2016·Antimicrobial Agents and Chemotherapy

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- 14 C]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 .

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  • Apart from binding their primary ligand, FeEnt, with high affinity, and its aposiderophore Ent with 100-200-fold lower affinity, KpnFepA_1658, KpnIroN, and KpnFepA_4984 showed different preferences for ferric catecholate complexes and siderophore antibiotics cefiderocol [FeFDC] and FeMB-1.

    “Apart from binding their primary ligand, FeEnt, with high affinity, and its aposiderophore Ent with 100-200-fold lower affinity (38), KpnFepA_1658, KpnIroN, and KpnFepA_4984 showed different preferences for ferric catecholate complexes and siderophore antibiotics cefiderocol [FeFDC (40,41)] and FeMB-1 (42,43):”

    From Siderophore-mediated iron acquisition by <i>Klebsiella pneumoniae</i> (2024) · cites this paper as [40]

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  1. [15]Griffiths E 1978 Iron in biological systems, p 1– 27. In Bullen JJ, Griffiths E (ed), Iron and infection. John Wiley & Sons, New York, NY.

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Authors
Ito, A., Nishikawa, T., Matsumoto, S., Yoshizawa, H., Sato, T., Nakamura, R., Tsuji, M., & Yamano, Y.
Affiliations
Shionogi (Japan) (JP)
Corresponding author
Ito, Akinobu
Venue
Antimicrobial Agents and Chemotherapy
Published
2016-12
Volume
60
Issue
12
Pages
7396-7401
ISSN
  • 0066-4804 (ISSN-L)
  • 1098-6596
OpenAlex
W2530661320
Cited by
352
References
33
Citations by year
2026: 52 · 2025: 34 · 2024: 35 · 2023: 37 · 2022: 40 · 2021: 37 · 2020: 41 · 2019: 29 · 2018: 30 · 2017: 16 · 2016: 1
FWCI
12.36
Type
journal article
Language
en
Open access
Locations
  • Antimicrobial Agents and Chemotherapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
Keywords
cefiderocol, siderophore cephalosporin, Pseudomonas aeruginosa, iron chelation, catechol moiety, iron depletion, intracellular accumulation, iron transporters, antibacterial activity, ceftazidime
MeSH terms
Cefiderocol, Anti-Bacterial Agents, Biological Transport, Carbon Radioisotopes, Ceftazidime, Cephalosporins, Fluoresceins, Fluorescent Dyes, Iron, Iron Chelating Agents, Microbial Sensitivity Tests, Pseudomonas aeruginosa, Structure-Activity Relationship, Thiazoles

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