title: In vitro antibacterial properties of T-5575 and T-5578 novel parenteral 2-carboxypenams.
abstract: T-5575 and T-5578, novel 2-carboxypenams in which a carboxyl group has been introduced into the C-2 beta position of the nucleus, were evaluated for their in vitro antibacterial properties. The spectrum of activity of T-5575 was similar to that of aztreonam. However, it showed stronger activities than those of aztreonam against most gram-negative bacteria. T-5575 also showed potent activities against isolates of Enterobacter cloacae, Citrobacter freundii, and Pseudomonas aeruginosa resistant to ceftazidime, with MICs at which 90% of the isolates were inhibited of 0.39, 0.39, and 3.13 microgram/ml, respectively. T-5578 showed moderate levels of activity against gram-negative bacteria, compared with those of T-5575. Its activity against P. aeruginosa, however, was superior to those of T-5575 and the reference drugs tested. The most characteristic feature of T-5578 was its potent activities against ceftazidime-, imipenem-, and gentamicin-resistant P. aeruginosa isolates, with MICs at which 90% of the isolates were inhibited at 0.39, 3.13, and 3.13 microgram/ml, respectively. These two compounds were unfortunately poorly active against gram-positive bacteria, such as Staphylococcus aureus and streptococci. Both compounds were found to be stable for hydrolysis by various kinds of beta-lactamases and to have low affinities for these enzymes, with Ki values of > 100 microM. These novel penams bound most tightly to penicillin-binding protein 3 of Escherichia coli and P. aeruginosa. These results indicate that T-5575 and T-5578 can be regarded as promising 2-carboxypenams specially targeted against gram-negative pathogens.
authors.affiliation: Research Laboratories, Toyama Chemical Co., Ltd, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Watanabe
authors.forename: S
authors.initials: S
authors.lastname: Minami
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: H
authors.initials: H
authors.lastname: Araki
authors.forename: R
authors.initials: R
authors.lastname: Kitayama
authors.forename: H
authors.initials: H
authors.lastname: Ochiai
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001398:Aztreonam / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology; D001424:Bacterial Infections / Q000382:microbiology; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D029968:Escherichia coli Proteins; D006602:Hexosyltransferases; D006801:Humans; D007769:Lactams; D008826:Microbial Sensitivity Tests; D008997:Monobactams / Q000494:pharmacology; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D046928:Peptidoglycan Glycosyltransferase; D010458:Peptidyl Transferases; D011485:Protein Binding; D001618:beta-Lactamases / Q000378:metabolism; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D002511:Cephalosporins; D029968:Escherichia coli Proteins; C478704:FtsI protein, E coli; D007769:Lactams; D008997:Monobactams; D046915:Penicillin-Binding Proteins; C097413:T 5575; C098323:T 5578; D047090:beta-Lactams; D002442:Ceftazidime; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D046928:Peptidoglycan Glycosyltransferase; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases; D001398:Aztreonam