Research paperCefiderocol (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
Introduction
In recent years, the threat of multidrug-resistant Gram-negative pathogens e.g. Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae is expanding all over the world [1,2]. The World Health Organization recently identified carbapenem resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae as the number 1 priority (critical) for which new antibiotics are needed [3]. The Review on Antimicrobial Resistance estimated that the number of deaths attributable to antimicrobial resistance could increase to 10 million each year by 2050, unless action is taken now [4]. Nevertheless, the therapeutic treatment options for infections caused by multi-drug resistant Gram-negative pathogens are severely limited [5]. Therefore, there is an urgent need for developing new and potent antibiotics targeting multi-drug resistant Gram-negative pathogens [6].
Microorganisms naturally secrete siderophores that are high affinity iron chelating compounds to acquire iron (Fe3+) effectively under an iron limited environment [[7], [7](a), [7](b)]. The major groups of siderophores include catechols, hydroxamates and carboxylates. For instance, enterobactin and pyoverdine secreted by E. coli and P. aeruginosa (1a and 1b, Fig. 1.) contain catechol groups as an iron chelating moiety [[8], [8](a), [8](b)].
One strategy to discover an antibiotic capable of eradicating multidrug-resistant Gram-negative pathogens is to utilize the bacterial iron (Fe3+) acquisition system to enhance the outer membrane penetration of Gram-negative bacteria through the attachment of an iron chelating moiety such as a catechol to the parent molecule [[9], [9](a), [9](b)]. This strategy was the focus of a number of research teams in 1980–90s and they reported that catechol or 4-pyridone conjugated β-lactam analogues had shown potent antibacterial activities against Gram-negative pathogens including P. aeruginosa [[10], [11], [12], [13], [14], [15], [16]]. However, none of those compounds reached clinical stage development. Our team identified in 1990s a catechol conjugated cephalosporin A-2 (2, Fig. 2) [17], which displayed potent activity against P. aeruginosa (see Table 1 for the in vitro activity), however compound 2 did not progress to clinical stage development due to poor physicochemical properties. We restarted in 2008 the drug discovery research of siderophore cephalosporins based on the structure and the activity of compound 2 to identify a new candidate with potent activities against several multi-drug resistant pathogens including new varieties of carbapenemase [[1], [2], [3]] (carbapenem-hydrolyzing enzyme) producing carbapenem resistant pathogens that had become a global health issue. Several analogues modified at the C-3 side chains (quaternary ammonium, amide linker and catechol moiety) and the C-7 side chains (aminothiazole and oxime moiety) were synthesized and evaluated in vitro and in vivo for antibacterial activities against Gram-negative pathogens (Fig. 2). Here, we report the SAR results of several siderophore cephalosporins that led to the selection of cefiderocol (3).
Section snippets
Chemistry
Fig. 3 outlines the two synthetic pathways of novel siderophore cephalosporins. An aminothiazolylacetic acid derivative as a C-7 side chain was coupled with a known cephalosporin nucleus ACLE·HCl (7-amino-3-chloromethyl-3-cephem-4-carboxylate p-methoxybenzyl ester hydrochloride) or ACLH·HCl (7-amino-3-chloromethyl-3-cephem-4-carboxylate benzhydryl ester hydrochloride) to introduce a C-7 side chain, followed by quaternization with a tertiary amine as a C-3 side chain to give a precursor of a new
Results and discussion
The minimum inhibitory concentrations (MICs) of the new siderophore cephalosporins against drug resistant Gram-negative pathogens were determined by broth microdilution method in cation-adjusted Mueller-Hinton broth supplemented with 20 μM human apo-transferrin to mimic the iron (Fe3+) deficiency condition present in acute infections [33,34]. The MIC values (μg/mL) of cefepime and meropenem were determined by broth microdilution method according to the Clinical and Laboratory Standards
Conclusion
In summary, we have described our structure activity relationship results of the catechol conjugated siderophore cephalosporin based on the structure of 2. Many compounds modified with the C-3 and C-7 side chain exhibited potent antibacterial activities against multi-drug resistant Gram-negative pathogens such as P. aeruginosa and A. baumannii. The presence of a cyclic quaternary ammonium moiety and a halogenated catechol group at the C-3 position of a siderophore cephalosporin dramatically
Chemistry
Reagents and solvents were purchased from commercial sources and used without purification. Reactions were carried out under a nitrogen atmosphere with anhydrous solvents. Reaction mixtures were monitored using thin-layer chromatography (TLC) on silica gel F254 TLC plates. Column chromatography was carried out using silica gel. Reverse phase column chromatography was carried out using HP20SS and octadecylsilyl Silica Gel (Yamazen ULTRA PACK). 1H NMR spectra were recorded on a Varian Gemini-300
Associated content
The experimental procedures for the preparation of the intermediates and the individual CAB assay date of the tested compounds are described in the Supplementary Information.
References (47)
- et al.
Update on the antibiotic resistance crisis
Curr. Opin. Pharmacol.
(2014) - et al.
Enterobactin: the characteristic catecholate siderophore of Enterobacteriaceae is produced by Streptomyces species
FEMS Microbiol. Lett.
(2001)Pyoverdines: pigments, siderophores and potential taxonomic markers of fluorescent Pseudomonas species
Arch. Microbiol.
(2000) - et al.
Sideromycins as pathogen-targeted antibiotics
et al.Targeting iron assimilation to develop new antibacterials
Expert Opin. Drug Discovery
(2012) - Becker, D. P.; Flynn, D. L.; Villamil, C. I. Indolones Useful as Serotonergic Agents....
- Peters, D.; Timmermann, D. B.; Nielsen, E. O.; Olsen, G. M.; Dyhring, T.; Christensen, J. K.; Redrobe, J. P.;...
- et al.
Synthesis and conformational properties of N-monoalkyl 1, 5-diaza-cis-decalins
Tetrahedron Lett.
(2001) - et al.
Synthesis and antibacterial activities of novel C(3)-aminopyrimidinyl substituted cephalosporins including against respiratory tract pathogens
Bioorg. Med. Chem. Lett
(2000) - et al.
Synthesis of 1,4,7,10-Tetra-azacyclododecan-1,4,7,10-tetra-azidoethylacetic acid (DOTAZA) and related “clickable” DOTA derivatives
Chem. Asian J.
(2014) - et al.
Synthesis and biological evaluation of a series of parenteral 3'-quaternary ammonium cephalosporins
J. Med. Chem.
(1990) - et al.
Discovery of efficacious Pseudomonas aeruginosa-targeted siderophore-conjugated monocarbams by application of a semi-mechanistic pharmacokinetic/pharmacodynamic model
J. Med. Chem.
(2015)
New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn?
Clin. Microbiol. Infect.
Infections caused by resistant gram-negative bacteria: epidemiology and management
Pharmacotherapy
WHO publishes list of bacteria for which new antibiotics are urgently needed
Multidrug-resistant Gram-negative infections: what are the treatment options?
Drugs
Fix the antibiotics pipeline
Nature
Chemistry and biology of siderophores
Nat. Prod. Rep.
Siderophores: structure and function of microbial iron transport compounds
J. Biol. Chem.
Semisynthetic β-lactam antibiotics effect on antibacterial activity and comtsusceptibility of chlorine-introduction into the catechol nucleus of 6-[(jr)-2-[3 -(3 ,4-Dihydroxybenzoyl)- 3 -(3 -hydroxypropyl)- L -ureid O]-2-Phenylacetamid O1penicillanic acid
J. Antibiot.
Synthesis and structure-activity relationships of cephalosporins with C-3’ catechol-containing residues
J. Med. Chem.
Antibacterial and pharmacokinetic properties of M14659, a new injectable semisynthetic cephalosporin
J. Antibiot.
Comparison of transport pathways of catechol-substituted cephalosporins, Bo-1236 and Bo-1341, through the outer membrane of Escherichia Coli
J. Antibiot.
Kond, New aminothiazolylglycylcephalosporins with a 1, 5-dihydroxy-4-pyridone-2-carbonyl group i. Synthesis and biological activity of cephalosporin derivatives leading to MT0703
J. Antibiot.
New aminothiazolylglycylcephalosporins with a 1, 5-dihydroxy-4-pyridone-2-carbonyl group ii. Synthesis and antibacterial activity of MT0703 and its diastereomers
J. Antibiot.
Cited by (104)
Improved synthesis and evaluation of preclinical pharmacodynamic parameters of a new monocyclic β-lactam DPI-2016
2024, Bioorganic and Medicinal Chemistry LettersCefiderocol: Clinical application and emergence of resistance
2024, Drug Resistance UpdatesRecent developments in the synthesis of hybrid heterocycles, a promising approach to develop multi-target antibacterial agents
2023, Journal of Molecular StructureMetallo-β-lactamase-mediated antimicrobial resistance and progress in inhibitor discovery
2023, Trends in MicrobiologyA new selective inhibitor for IMP-1 metallo-β-lactamase, 3Z,5E-octa-3,5-diene-1,3,4-tricarboxylic acid-3,4-anhydride
2023, Bioorganic and Medicinal ChemistryCitation Excerpt :To improve effectiveness against IMP-1 MBL-producing P. aeruginosa, we focused on a system that enhances uptake by using iron-chelating siderophores with a high-affinity for ion for growing the bacteria under an ion limited environment25–27. Notably, cefiderocol, which has a catechol scaffold as an iron chelating moiety, was reported to be one of the best molecules that displayed potent activities against multi-drug resistant Gram-negative pathogens.28 Thus, we expected that the introduction of catechol moiety into the ODTAA scaffold would be highly effective against IMP-1 MBL-producing P. aeruginosa.