Stability of Novel Siderophore Cephalosporin S-649266 against Clinically Relevant Carbapenemases

Ito-Horiyama, Tsukasa; Ishii, Yoshikazu; Ito, Akinobu; Sato, Takafumi; Nakamura, Rio; Fukuhara, Norio; Tsuji, Masakatsu; Yamano, Yoshinori; Yamaguchi, Keizo; Tateda, Kazuhiro

doi:10.1128/aac.03098-15

Cited by 148 publications

(114 citation statements)

References 12 publications

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“…1) [48, 49]. Recently, several siderophores conjugated with β-lactam antibiotics have been evaluated in preclinical and clinical phases, including MC-1 (monocarbam), BAL30072 (monosulfactam) [50], S-649266 (cephalosporin) [51, 52] and GSK3342830 (cephalosporin), which target multidrug-resistant Gram-negative bacteria including A. baumannii and P. aeruginosa (Figure 3, right). P. aeruginosa is a particularly challenging pathogen to treat as it is intrinsically resistant to many antibiotics and easily acquires resistance (Table 1) [42, 53].…”

Section: Using Siderophores To Combat Bacterial Infectionmentioning

confidence: 99%

Siderophores in Iron Metabolism: From Mechanism to Therapy Potential

Wilson

Bogdan

Miyazawa

et al. 2016

Trends in Molecular Medicine

353

319

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Iron is an essential nutrient for life. During infection, a fierce battle of iron acquisition occurs between the host and bacterial pathogens. Bacteria acquire iron by secreting siderophores, small ferric iron binding molecules. In response, host immune cells secrete lipocalin 2 (also known as siderocalin), a siderophore-binding protein, to prevent bacterial reuptake of iron-loaded siderophores. To counter this threat, some bacteria can produce lipocalin 2-resistant siderophores. This review discusses the recently described molecular mechanisms of siderophore iron trafficking between host and bacteria, highlighting the therapeutic potential of exploiting pathogen siderophore machinery for the treatment of antibiotic-resistant bacterial infections. As the latter reflect a persistent problem in hospital settings, siderophore-targeting or siderophore-based compounds represent a promising avenue to combat such infections.

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Section: Using Siderophores To Combat Bacterial Infectionmentioning

confidence: 99%

Siderophores in Iron Metabolism: From Mechanism to Therapy Potential

Wilson

Bogdan

Miyazawa

et al. 2016

Trends in Molecular Medicine

353

319

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“…aeruginosa, and Acinetobacter baumannii (24–27). We have shown that this potent activity of cefiderocol is partly due to its high stability against various extended-spectrum β-lactamases (ESBLs) and carbapenemases (26, 28). In this study, the underlying active uptake mechanisms of cefiderocol leading to the in vitro activity against P.…”

Section: Introductionmentioning

confidence: 99%

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

Ito

Nishikawa

Matsumoto

et al. 2016

Antimicrob Agents Chemother

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251

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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.

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“…Once across the outer membrane, the iron dissociates and the cephalosporin binds to penicillin-binding proteins (PBP), mainly PBP3, as other cephalosporins do to disrupt cell wall synthesis [11,13], contributing to a potent antimicrobial activity against Gram-negative bacteria. In addition, this antimicrobial activity of cefiderocol is enhanced by the high stability of cefiderocol to hydrolysis by nearly all β-lactamases, including both the serine and metallo-carbapenemases [14]. The ability to cross the outer membrane through the active iron-transport system overcomes resistance due to porin channel mutations and efflux pump overproducers.…”

Section: Introductionmentioning

confidence: 99%

Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

Dobiáš

Denervaud-Tendon

Poirel

et al. 2017

Eur J Clin Microbiol Infect Dis

135

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The novel siderophore cephalosporin cefiderocol (S-649266) with potent activity against Gram-negative pathogens was recently developed (Shionogi & Co., Ltd.). Here, we evaluated the activity of this new molecule and comparators against a collection of previously characterized Gram-negative isolates using broth microdilution panels. A total of 753 clinical multidrug-resistant Gram-negative isolates collected from hospitals worldwide were tested against cefiderocol and antibiotic

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Stability of Novel Siderophore Cephalosporin S-649266 against Clinically Relevant Carbapenemases

Cited by 148 publications

References 12 publications

Siderophores in Iron Metabolism: From Mechanism to Therapy Potential

Siderophores in Iron Metabolism: From Mechanism to Therapy Potential

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

Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

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