title: 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.
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan akinobu.ito@shionogi.co.jp.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Ito
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Shuhei
authors.identifier: 0000-0003-0377-8304
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yoshizawa
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Rio
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Tsuji
authors.affiliation: Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamano
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D002250:Carbon Radioisotopes; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D007501:Iron / Q000378:metabolism* / Q000633:toxicity; D007502:Iron Chelating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D000097602:Cefiderocol
chemical_list: D000900:Anti-Bacterial Agents; D002250:Carbon Radioisotopes; D002442:Ceftazidime; D002511:Cephalosporins; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007501:Iron; D007502:Iron Chelating Agents; D013844:Thiazoles; D000097602:Cefiderocol; C085925:calcein AM