title: In vitro activities of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems with potent activities against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.
abstract: The in vitro activities of the novel 1beta-methylcarbapenems J-111, 225, J-114,870, and J-114,871, which have a structurally unique side chain that consists of a trans-3,5-disubstituted 5-arylpyrrolidin-3-ylthio moiety at the C-2 position, were compared with those of reference antibiotics. Among isolates of both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS), 90% were inhibited by J-111,347 (prototype), J-111,225, J-114,870, and J-114,871 at concentrations of 2, 4, 4, and 4 microgram/ml (MICs at which 90% of isolates are inhibited [MIC(90)s]), respectively, indicating that these agents were 32- to 64-fold more potent than imipenem, which has an MIC(90) of 128 microgram/ml. Although these drugs were less active in vitro than vancomycin, which had MIC(90)s of 1 and 2 microgram/ml for MRSA and MRCoNS, respectively, the new carbapenems displayed better killing kinetics than vancomycin. The potent anti-MRSA activity was ascribed to the excellent affinities of the new carbapenems for penicillin-binding protein 2a of MRSA. Since the new carbapenems also exhibited good activity against gram-positive and -negative bacteria including clinically important pathogens such as penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Clostridium difficile, as well as MRSA, the novel carbapenems are worthy of further evaluation.
authors.affiliation: Banyu Tsukuba Research Institute, Okubo 3, Tsukuba 300-2611, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Nagano
authors.forename: K
authors.initials: K
authors.lastname: Shibata
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.forename: H
authors.initials: H
authors.lastname: Imamura
authors.forename: T
authors.initials: T
authors.lastname: Hashizume
authors.forename: H
authors.initials: H
authors.lastname: Morishima
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins; D015780:Carbapenems / Q000494:pharmacology*; D002352:Carrier Proteins; D003030:Coagulase / Q000378:metabolism; D015169:Colony Count, Microbial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006602:Hexosyltransferases; D006801:Humans; D015378:Imipenem / Q000494:pharmacology; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D013845:Thienamycins / Q000494:pharmacology; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D002352:Carrier Proteins; D003030:Coagulase; C404721:J 111225; C404722:J 114870; D046915:Penicillin-Binding Proteins; D013845:Thienamycins; D014640:Vancomycin; D015378:Imipenem; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase