In Vitro Activities of ME1036 (CP5609), a Novel Parenteral Carbapenem, against Methicillin-Resistant Staphylococci

Kurazono, Mizuyo; Ida, Takashi; Yamada, Keiko; Hirai, Yoshimasa; Maruyama, Takahisa; Shitara, Eiki; Yonezawa, Minoru

doi:10.1128/aac.48.8.2831-2837.2004

Cited by 40 publications

(27 citation statements)

References 19 publications

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“…3 For the study reported herein, ME1036 was found to have potent anitbacterial activity against genotypic PRSPs (gPRSPs) that are resistant to b-lactams due to mutated pbps. In particular, the strong binding affinities of antibiotics for PBP1A, PBP2X and PBP2B from gPRSP is thought to be basis for its strong antibacterial activities.…”

Section: Discussionmentioning

confidence: 93%

“…ME1036 ( Figure 1) is a new broad-spectrum parenteral carbapenem that is active against multi-drug resistant Gram-positive and Gramnegative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum b-lactamase-producing Enterobacteriaceae. 3 The study reported herein was designed to evaluate the relationship between the binding affinities of ME1036 for wild-type and mutant penicillin-binding proteins (PBPs) and its efficacy against S. pneumoniae strains containing those PBPs.…”

Section: The Emergence Of Penicillin-intermediate and Penicillin-resimentioning

confidence: 99%

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Correlation of the antimicrobial activity of ME1036 with its binding affinities to the penicillin-binding proteins from Streptococcus pneumoniae strains

Hirai¹,

Takahata²,

Yamada³

et al. 2011

J Antibiot

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We have correlated the binding affinities of ME1036, a carbapenem, to the penicillin-binding proteins (PBPs) from Streptococcus pneumoniae strains, with its bactericidal potency against those same strains. Certain mutations in the PBPs from S. pneumonaie strains decrease the binding affinities of b-lactams for PBPs, which gives rise to clinical resistance to those b-lactams. ME1036 has been shown to be strongly active against genotypic penicillin-intermediate S. pneumoniae (gPISP) strains and genotypic penicillin-resistant S. pneumoniae (gPRSP) strains that contain more than one mutation in their PBPs, owing to its strong affinity for those PBPs.

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Section: Discussionmentioning

confidence: 93%

Section: The Emergence Of Penicillin-intermediate and Penicillin-resimentioning

confidence: 99%

Correlation of the antimicrobial activity of ME1036 with its binding affinities to the penicillin-binding proteins from Streptococcus pneumoniae strains

Hirai¹,

Takahata²,

Yamada³

et al. 2011

J Antibiot

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“…Instead of increasing the angular strain and the N1 pyramidality (''twisted amide'') in the azetidinone ring of 1,4-fused bi- [64,65] or tricyclic systems [66], we considered flexible 1,3-bridged bicyclic systems featuring a ''planar amide'' and a large ring susceptible to generate a lot of conformers. Such azetidinones, endowed with a thienamycin-like side-chain at C3 and the related stereochemistry at C3-C5, are readily accessible via a convergent RCM strategy, as illustrated by the synthesis of the 13-membered bicycles E-11 and 12 from the commercial chiron 7, precursor of 10.…”

Section: Discussionmentioning

confidence: 99%

“…Particularly, the prevalence of MRSA (methicillin-resistant Staphylococcus aureus) in hospitals has stimulated the development of more potent carbapenems (ME 1036 [64]) and cephalosporins (PPI 0903M [65]), characterized by very bulky substituents on the bicyclic skeletons. The lethal action of such antibiotics is due to their high affinity for PBP 2a .…”

Section: Discussionmentioning

confidence: 99%

Large ring 1,3-bridged 2-azetidinones: Experimental and theoretical studies

Urbach

Dive

Tinant

et al. 2009

European Journal of Medicinal Chemistry

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a b s t r a c tThe relationship between angular strain and (re)activity of bicyclic 2-azetidinones is still an open question of major concern in the field of penicillin antibiotics. Our study deals with original 13-membered-ring 1,3-bridged 2-azetidinones related to the carbapenem family, and featuring a ''planar amide'' instead of the ''twisted amide'' typical of penam derivatives. The bicycles 11 and 12 were obtained from acetoxy-azetidinone 7, via the key-intermediate 10, by using the RCM (ring closing metathesis) strategy. Theoretical predictions and experimental results of hydrolysis showed that the large bicycle 12, endowed with high conformational flexibility, is more reactive than the bicycle 11, including a C]C bond of E configuration, and the monocyclic 2-azetidinone precursor 10. The processing of 2-azetidinones 10-12 in the active site of serine enzymes has been computed by ab initio methods, considering three models. Due to geometrical parameters of the enzymic cavity (nucleophilic attack from the a-face), precursor 10 was predicted more active than 11 and 12 in the acylation step by Ser-OH.Indeed, bicycles 11 and 12 are modest inhibitors of PBP 2a , while 10 is a good to excellent inhibitor of PBP 2a and R39 bacterial enzymes.

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“…ME1036, a novel parenteral carbapenem, was developed to combat MRSA or VISA [3][4], and it is expected to be useful for the treatment of severe staphylococcal infections such as pneumonia, bacteremia, and pulmonary abscesses.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of ME1036 against meticillin-resistant Staphylococcus aureus and vancomycin-insensitive S. aureus in a model of haematogenous pulmonary infection

Yanagihara¹,

Ohnishi²,

Morinaga³

et al. 2008

International Journal of Antimicrobial Agents

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In Vitro Activities of ME1036 (CP5609), a Novel Parenteral Carbapenem, against Methicillin-Resistant Staphylococci

Cited by 40 publications

References 19 publications

Correlation of the antimicrobial activity of ME1036 with its binding affinities to the penicillin-binding proteins from Streptococcus pneumoniae strains

Correlation of the antimicrobial activity of ME1036 with its binding affinities to the penicillin-binding proteins from Streptococcus pneumoniae strains

Large ring 1,3-bridged 2-azetidinones: Experimental and theoretical studies

Efficacy of ME1036 against meticillin-resistant Staphylococcus aureus and vancomycin-insensitive S. aureus in a model of haematogenous pulmonary infection

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