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

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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
DOI 10.1128/aac.01405-16PMC PMC5119021
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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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Crossref · 10.1128/aac.01405-16

Cites

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Figures

FIG 1 Chemical structures of cefiderocol, cefiderocol catechol 3-methoxy, and ceftazidime.
FIG 1 Chemical structures of cefiderocol, cefiderocol catechol 3-methoxy, and ceftazidime.CC BY · PubMed Central
FIG 2 Uptake of [thiazole-14C]cefiderocol into P. aeruginosa PAO1. The test strain was incubated under iron-depleted (ID-CAMHB) and iron-sufficient [ID-CAMHB supplemented with 100 μM ammonium iron(III) citrate] conditions overnight. After the culture was washed and incubated at 37°C for 10 min, 66 μM ammonium iron(III) citrate and 10 μg/ml [thiazole-14C]cefiderocol were simultaneously added. Samples were taken at 0.5, 1, 3, 5, and 10 min and filtered, and the radioactivity was determined by a liquid scintillation counter. The uptake amounts of [thiazole-14C]cefiderocol were significantly different between the cells grown in ID-CAMHB and those grown in CAMHB at all time points (P value < 0.05, by t test).
FIG 2 Uptake of [thiazole-14C]cefiderocol into P. aeruginosa PAO1. The test strain was incubated under iron-depleted (ID-CAMHB) and iron-sufficient [ID-CAMHB supplemented with 100 μM ammonium iron(III) citrate] conditions overnight. After the culture was washed and incubated at 37°C for 10 min, 66 μM ammonium iron(III) citrate and 10 μg/ml [thiazole-14C]cefiderocol were simultaneously added. Samples were taken at 0.5, 1, 3, 5, and 10 min and filtered, and the radioactivity was determined by a liquid scintillation counter. The uptake amounts of [thiazole-14C]cefiderocol were significantly different between the cells grown in ID-CAMHB and those grown in CAMHB at all time points (P value < 0.05, by t test).CC BY · PubMed Central
FIG 3 Chelating activity of cefiderocol with ferric iron determined by chrome azurol B. The chelating activity was determined by the color change of chrome azurol B in the presence of cetyltrimethylammonium bromide. The color change was detected by measuring the A630 with a spectrophotometer. The chelating activities were significantly different between cefiderocol and ceftazidime and between cefiderocol and cefiderocol catechol 3-methoxy at concentrations of 10, 30, 100, 300, and 1,000 μM (P value < 0.05, by t test). The chelating activities were also significantly different between pyoverdine and ceftazidime and between pyoverdine and cefiderocol catechol 3-methoxy at concentrations of 3, 10, 30, and 100 μM (P value < 0.05, by t test).
FIG 3 Chelating activity of cefiderocol with ferric iron determined by chrome azurol B. The chelating activity was determined by the color change of chrome azurol B in the presence of cetyltrimethylammonium bromide. The color change was detected by measuring the A630 with a spectrophotometer. The chelating activities were significantly different between cefiderocol and ceftazidime and between cefiderocol and cefiderocol catechol 3-methoxy at concentrations of 10, 30, 100, 300, and 1,000 μM (P value < 0.05, by t test). The chelating activities were also significantly different between pyoverdine and ceftazidime and between pyoverdine and cefiderocol catechol 3-methoxy at concentrations of 3, 10, 30, and 100 μM (P value < 0.05, by t test).CC BY · PubMed Central
FIG 4 Iron uptake by P. aeruginosa PAO1 detected by calcein fluorescence intensity in the cells. Calcein-AM was added to the overnight culture in iron-depleted medium (ID-CAMHB); the culture was incubated for 120 min, and green fluorescence intensity was monitored by an EnVision Multilabel reader with 492-nm excitation and 535-nm emission. During 300 s of monitoring, 50 μg/ml of the compound was added 90 s after the initiation of the monitoring.
FIG 4 Iron uptake by P. aeruginosa PAO1 detected by calcein fluorescence intensity in the cells. Calcein-AM was added to the overnight culture in iron-depleted medium (ID-CAMHB); the culture was incubated for 120 min, and green fluorescence intensity was monitored by an EnVision Multilabel reader with 492-nm excitation and 535-nm emission. During 300 s of monitoring, 50 μg/ml of the compound was added 90 s after the initiation of the monitoring.CC BY · PubMed Central

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Citations

Cites

Show all 33 references

Research works printed but not linked: 4

  1. 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.
  2. Nakamura R, Toba S, Tsuji M, Yamano Y, Shimada J. 2014. S-649266, a novel siderophore cephalosporin. IV: in vivo efficacy in various murine infection models, abstr F1-1558. Abstr 54th Intersci Conf Antimicrob Agents Chemother, American Society for Microbiology, Washington, DC.
  3. Nakamura R, Toba S, Ito A, Tsuji M, Yamano Y, Shimada J. 2014. S-649266, a novel siderophore cephalosporin. V: pharmacodynamic assessment in murine thigh infection models, abstr F1-1559. Abstr 54th Intersci Conf Antimicrob Agents Chemother, American Society for Microbiology, Washington, DC.
  4. Müller C, Hofer B, Desarbre E, Page MGP. 2010. Enhanced activity of the siderophore monosulfactam BAL30072 (BAL) against Acinetobacter in iron-limited conditions, abstr F1-2133. Abstr 50th Intersci Conf Antimicrob Agents Chemother, American Society for Microbiology, Washington, DC.

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Metadata

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
ORCID
Venue
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Published
2016-12
Volume
60
Issue
12
Pages
7396-7401
ISSN
  • 0066-4804 (ISSN-L)
  • 1098-6596
DOI
10.1128/aac.01405-16
PMC
PMC5119021
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
Licence
Locations
  • Antimicrobial Agents and Chemotherapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Health Sciences › Medicine › Pharmacology (medical) › 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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