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

Aoki, Toshiaki; Yoshizawa, Hidekazu; Yamawaki, Kenji; Yokoo, Katsuki; Sato, Jun; Hisakawa, Shinya; Hasegawa, Yasushi; Kusano, Hiroki; Sano, Masayuki; Sugimoto, Hideki; Nishitani, Yasuhiro; Sato, Takafumi; Tsuji, Masakatsu; Nakamura, Rio; Nishikawa, Toru; Yamano, Yoshinori

doi:10.1016/j.ejmech.2018.06.014

Cited by 114 publications

(93 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The catecholate‐type siderophore cephalosporin ( 21 ) exhibited potent antibacterial activity against multidrug resistance (MDR) Gram‐negative bacteria (eg, P. aeruginosa , A. baumannii , K. pneumoniae , and E. coli ), including in carbapenem‐resistant strains (Table ). Cefiderocol also exhibited potent in vivo efficacy against MDR P. aeruginosa in a model of systemic mouse infection . In addition, the pharmacokinetics (PK) safety and tolerability thresholds, ( 21 ) after both single and multiple dosing through intravenous infusion, over a period of 60 minutes in healthy adult subjects, were studied .…”

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

“…78 Cefiderocol (21, Figure 5), also known as S-649266, is one of the most promising drug candidates for siderophore-β-lactam conjugates, which were recently developed by Shionogi & Co, Ltd (Osaka, Japon). 96 The catecholate-type siderophore cephalosporin (21) exhibited potent antibacterial activity against multidrug resistance (MDR) Gram-negative bacteria (eg, P. aeruginosa, A. baumannii, K. pneumoniae, and E. coli), including in carbapenem-resistant strains (Table 3). Cefiderocol also exhibited potent in vivo efficacy against MDR P. aeruginosa in a model of systemic mouse infection.…”

mentioning

confidence: 99%

“…Cefiderocol also exhibited potent in vivo efficacy against MDR P. aeruginosa in a model of systemic mouse infection. 96 In addition, the pharmacokinetics (PK) safety and tolerability thresholds, (21) after both single and multiple dosing through intravenous infusion, over a period of 60 minutes in healthy adult subjects, were studied. 97 The results indicate that single and multiple intravenous doses (ranging from 100 up to 2000 mg) were well tolerated in healthy subjects.…”

mentioning

confidence: 99%

“…200 The obtained CPP-gentamicin conjugates (96)(97)(98) were firstly evaluated against multiple intracellular pathogens including E. coli K1, Salmonella enterica serovar Typhimurium, and Shigella flexneri (Table 12). 200 The results showed that the CPP-gentamicin conjugates (96)(97)(98) were capable of retaining their ATB activity when compared to the parent antibiotic gentamicin. Subsequently, the ability of the CPPs to deliver the gentamicin-cargo (94) into bacteria-infected mammalian cells and the ATB effect of CPP-gentamicin conjugates were investigated.…”

mentioning

confidence: 99%

“…Because of this, oxazolidinones are effective as Gram-positive antibiotics, but are not effective against a majority of Gram-negative pathogens. The T A B L E 3 In vitro bacterial activity of cefiderocol, cefepime and meropenem against Gram-negative bacteria96…”

mentioning

confidence: 99%

See 4 more Smart Citations

Drug delivery systems designed to overcome antimicrobial resistance

Pham

Loupias

Dassonville‐Klimpt

et al. 2019

Medicinal Research Reviews

View full text Add to dashboard Cite

Antimicrobial resistance has emerged as a huge challenge to the effective treatment of infectious diseases. Aside from a modest number of novel anti‐infective agents, very few new classes of antibiotics have been successfully developed for therapeutic use. Despite the research efforts of numerous scientists, the fight against antimicrobial (ATB) resistance has been a longstanding continued effort, as pathogens rapidly adapt and evolve through various strategies, to escape the action of ATBs. Among other mechanisms of resistance to antibiotics, the sophisticated envelopes surrounding microbes especially form a major barrier for almost all anti‐infective agents. In addition, the mammalian cell membrane presents another obstacle to the ATBs that target intracellular pathogens. To negotiate these biological membranes, scientists have developed drug delivery systems to help drugs traverse the cell wall; these are called “Trojan horse” strategies. Within these delivery systems, ATB molecules can be conjugated with one of many different types of carriers. These carriers could include any of the following: siderophores, antimicrobial peptides, cell‐penetrating peptides, antibodies, or even nanoparticles. In recent years, the Trojan horse‐inspired delivery systems have been increasingly reported as efficient strategies to expand the arsenal of therapeutic solutions and/or reinforce the effectiveness of conventional ATBs against drug‐resistant microbes, while also minimizing the side effects of these drugs. In this paper, we aim to review and report on the recent progress made in these newly prevalent ATB delivery strategies, within the current context of increasing ATB resistance.

show abstract

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Drug delivery systems designed to overcome antimicrobial resistance

Pham

Loupias

Dassonville‐Klimpt

et al. 2019

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

show abstract

Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species**

Jung,

Kraimps,

Dittmann

et al. 2023

ChemBioChem

View full text Add to dashboard Cite

Fidaxomicin (Fdx) is a natural product antibiotic with potent activity against Clostridioides difficile and other Gram‐positive bacteria such as Mycobacterium tuberculosis. Only few Fdx derivatives have been synthesized and examined for their biological activity in the 50 years since its discovery. Fdx has a well‐studied mechanism of action, namely inhibition of the bacterial RNA polymerase. Yet, the targeted organisms harbor different target protein sequences, which poses a challenge for the rational development of new semisynthetic Fdx derivatives. We introduced substituents on the two phenolic hydroxy groups of Fdx and evaluated the resulting trends in antibiotic activity against M. tuberculosis, C. difficile, and the Gram‐negative model organism Caulobacter crescentus. As suggested by the target protein structures, we identified the preferable derivatisation site for each organism. The derivative ortho‐methyl Fdx also exhibited activity against the Gram‐negative C. crescentus wild type, a first for fidaxomicin antibiotics. These insights will guide the synthesis of next‐generation fidaxomicin antibiotics.

show abstract

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

Cited by 114 publications

References 39 publications

Drug delivery systems designed to overcome antimicrobial resistance

Drug delivery systems designed to overcome antimicrobial resistance

Medicinal Chemistry of β‐Lactam Antibiotics

Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species**

Contact Info

Product

Resources

About