TAK-599, a novel N-Phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties

Ishikawa, Tomoyasu; Matsunaga, Nobuyuki; Tawada, Hiroyuki; Kuroda, Noritaka; Nakayama, Yutaka; Ishibashi, Yukio; Tomimoto, Mitsumi; Ikeda, Yukihiro; Tagawa, Yoshihiko; Iizawa, Yuji; Okonogi, Kenji; Hashiguchi, Shohei; Miyake, Akio

doi:10.1016/s0968-0896(03)00126-3

Cited by 125 publications

(77 citation statements)

References 13 publications

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“…As will be discussed below, Ser-403 is well sheltered within the active site and its side chain hydroxyl is in contact with the side chain of Lys-406 (8). This arrangement of Ser-X-X-Lys for PBPs and related ␤-lactamases is understood to be important for the mechanisms of these enzymes (30).…”

Section: Resultsmentioning

confidence: 99%

The Basis for Resistance to β-Lactam Antibiotics by Penicillin-binding Protein 2a of Methicillin-resistant Staphylococcus aureus

Fuda

Suvorov

Vakulenko

et al. 2004

Journal of Biological Chemistry

221

200

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Penicillin-binding protein 2a (PBP2a) of Staphylococcus aureus is refractory to inhibition by available ␤-lactam antibiotics, resulting in resistance to these antibiotics. The strains of S. aureus that have acquired the mecA gene for PBP2a are designated as methicillin-resistant S. aureus (MRSA). The mecA gene was cloned and expressed in Escherichia coli, and PBP2a was purified to homogeneity. The kinetic parameters for interactions of several ␤-lactam antibiotics (penicillins, cephalosporins, and a carbapenem) and PBP2a were evaluated. The enzyme manifests resistance to covalent modification by ␤-lactam antibiotics at the active site serine residue in two ways. First, the microscopic rate constant for acylation (k 2 ) is attenuated by 3 to 4 orders of magnitude over the corresponding determinations for penicillinsensitive penicillin-binding proteins. Second, the enzyme shows elevated dissociation constants (K d ) for the non-covalent pre-acylation complexes with the antibiotics, the formation of which ultimately would lead to enzyme acylation. The two factors working in concert effectively prevent enzyme acylation by the antibiotics in vivo, giving rise to drug resistance. Given the opportunity to form the acyl enzyme species in in vitro experiments, circular dichroism measurements revealed that the enzyme undergoes substantial conformational changes in the course of the process that would lead to enzyme acylation. The observed conformational changes are likely to be a hallmark for how this enzyme carries out its catalytic function in cross-linking the bacterial cell wall.

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Section: Resultsmentioning

confidence: 99%

The Basis for Resistance to β-Lactam Antibiotics by Penicillin-binding Protein 2a of Methicillin-resistant Staphylococcus aureus

Fuda

Suvorov

Vakulenko

et al. 2004

Journal of Biological Chemistry

221

200

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“…Previous papers using comparable techniques reported average IC 50 s of 0.16 to 0.9 g/ml for ceftaroline in MRSA strains (27,42,64). Differences between our results and those reported previously (27) may be explained at least partially by differences in strains and culture conditions.…”

Section: Vol 54 2010 Ceftaroline Affinity For Gram-positive Pbps 1671mentioning

confidence: 89%

Affinity of Ceftaroline and Other β-Lactams for Penicillin-Binding Proteins from Staphylococcus aureus and Streptococcus pneumoniae

Kosowska-Shick

McGhee

Appelbaum

2010

Antimicrob Agents Chemother

162

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We compared the affinities of ceftaroline for all penicillin-binding proteins (PBPs) with those of ceftriaxone and cefotaxime in 6 Staphylococcus aureus and 7 Streptococcus pneumoniae isolates with various resistance phenotypes. Ceftaroline MICs were <1 g/ml against all S. aureus isolates and were <0.25 g/ml for 4 of 7 isolates of S. pneumoniae. Ceftaroline affinities for penicillin-susceptible S. pneumoniae strains were in the order PBP2X and -3 > PBP1A, -1B, and -2A > PBP2B, and ceftaroline had >4-fold higher 50% inhibitory concentrations (IC 50 s) (0.1 to 4 g/ml) for PBP2X, -2A, -2B, and -3 than those for the other cephalosporins tested. Among 3 penicillin-resistant S. pneumoniae strains, ceftaroline had a high affinity for PBP2X (IC 50 , 0.1 to 1 g/ml), a primary target for cephalosporin PBP binding activity, and high affinities for PBP2B (IC 50 , 0.5 to 4 g/ml) and PBP1A (IC 50 , 0.125 to 0.25 g/ml) as well, both of which are also known as major targets for PBP binding activity of cephalosporins. Ceftaroline PBP affinities in methicillin-susceptible S. aureus strains were greater than or equal to those of the 3 other ␤-lactams tested. Ceftaroline bound to PBP2a in methicillinresistant S. aureus (IC 50 , 0.01 to 1 g/ml) with up to 256-fold-higher affinity than those of other agents. Ceftaroline demonstrated very good PBP affinity against all S. aureus and S. pneumoniae strains tested, including resistant isolates.␤-Lactam antibiotics exert their antibacterial effect through covalent interactions with penicillin-binding proteins (PBPs), thus blocking the terminal step in cell wall biosynthesis. ␤-Lactam resistance in Streptococcus pneumoniae is usually caused by amino acid substitutions in the penicillin-binding domains of 1 or more of its 6 PBPs, resulting from point mutations or mosaic genes following recombination (21)(22)(23)35). Altered PBP1A, PBP2X, and PBP2B are the most important PBPs for ␤-lactam resistance among clinical pneumococcal isolates (2,3,31,46,57).In staphylococci, PBPs 1, 2, and 3, which have high affinities for most ␤-lactam antibiotics, are essential for cell growth and survival of methicillin-susceptible strains. Binding of ␤-lactams by these PBPs is lethal (6). Low-molecular-weight PBP4, although it may be important in normal cell wall synthesis and may participate to a limited extent in resistance, is not considered a critical target and may be dispensable (17,41). Methicillin resistance in methicillin-resistant staphylococci (MRSA) is due to expression of a special PBP, PBP2a, which is not present in methicillin-susceptible staphylococci (6,58,59).Ceftaroline fosamil is the developmental intravenous prodrug form of the broad-spectrum cephalosporin ceftaroline (formerly called PPI-0903 M or TAK-91825), which is active against MRSA and has a high affinity for PBP2a (PBP2Ј). It is also active against streptococci, including S. pneumoniae (3,15,16,43,45).In the current study, we determined the affinities of ceftaroline, ceftriaxone, cefotaxime, and penicillin G for PBPs from 6Staphyloco...

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“…As part of a new generation of cephalosporins, ceftaroline fosamil is a broad-spectrum antibiotic approved by the FDA for the treatment of respiratory tract and wound infections [5][6][7]. Ceftaroline's effectiveness is related to its high binding affinity to modified penicillin-binding proteins as compared with other β-lactam antibiotics.…”

Section: Discussionmentioning

confidence: 99%

“…Because of these considerations, there will continue to be studies to observe developing antibiotic resistance and to identify new and more efficient treatment options [2,3]. As part of a new generation of cephalosporins, ceftaroline fosamil is a broad-spectrum antibiotic approved by the United States Food and Drug Administration (FDA) for the treatment of respiratory tract and wound infections [5][6][7]. Our study aimed to investigate the effectiveness of the new generation of cephalosporins such as ceftaroline against frequently encountered respiratory tract and wound infection agents using the microdilution method.…”

Section: Introductionmentioning

confidence: 99%

Ceftaroline activity on certain respiratory tract and wound infection agents at the minimum inhibitory concentration level

Yanık

Guluzade

Bılgın

et al. 2015

J Infect Dev Ctries

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Introduction: The aim of this study was to investigate the effectiveness of ceftaroline against agents frequently isolated from respiratory tract and wound infections. Methodology: The study included a total of 250 strains isolated from various clinical specimens, among which were Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysagalactiae, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catharralis. The bacteria were identified using the matrix-assisted laser desorption/ionization time-of-flight method and conventional methods. The bacteria's antibiotic susceptibility was tested using appropriate broth microdilution. Mueller-Hinton broth with 4% lysed horse blood, Haemophilus test medium broth, and Mueller-Hinton broth were used. Ceftaroline fosamil results at the minimum inhibitory concentration (MIC) were evaluated using Clinical and Laboratory Standards Institute (CLSI) criteria.

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TAK-599, a novel N-Phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties

Cited by 125 publications

References 13 publications

The Basis for Resistance to β-Lactam Antibiotics by Penicillin-binding Protein 2a of Methicillin-resistant Staphylococcus aureus

The Basis for Resistance to β-Lactam Antibiotics by Penicillin-binding Protein 2a of Methicillin-resistant Staphylococcus aureus

Affinity of Ceftaroline and Other β-Lactams for Penicillin-Binding Proteins from Staphylococcus aureus and Streptococcus pneumoniae

Ceftaroline activity on certain respiratory tract and wound infection agents at the minimum inhibitory concentration level

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