title: In vitro and in vivo activities of AM-112, a novel oxapenem.
abstract: AM-112 [(1'R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate] is a novel oxapenem compound which possesses potent beta-lactamase-inhibitory properties. Fifty-percent inhibitory concentrations (IC(50)s) of AM-112 for class A enzymes were between 0.16 and 2.24 micro M for three enzymes, compared to IC(50)s of 0.008 to 0.12 micro M for clavulanic acid. Against class C and class D enzymes, however, the activity of AM-112 was between 1,000- and 100,000-fold greater than that of clavulanic acid. AM-112 had affinity for the penicillin-binding proteins (PBPs) of Escherichia coli DC0, with PBP2 being inhibited by the lowest concentration of AM-112 tested, 0.1 micro g/ml. Ceftazidime was combined with AM-112 at 1:1 and 2:1 ratios in MIC determination studies against a panel of beta-lactamase-producing organisms. These studies demonstrated that AM-112 was effective at protecting ceftazidime against extended-spectrum beta-lactamase-producing strains and derepressed class C enzyme producers, reducing ceftazidime MICs by 16- and 2,048-fold. Similar results were obtained when AM-112 was combined with ceftriaxone, cefoperazone, or cefepime in a 1:2 ratio. Protection of ceftazidime with AM-112 was maintained against Enterobacter cloacae P99 and Klebsiella pneumoniae SHV-5 in a murine intraperitoneal sepsis model. The 50% effective dose of ceftazidime against E. cloacae P99 and K. pneumoniae SHV-5 was reduced from >100 and 160 mg/kg of body weight to 2 and 33.6 mg/kg, respectively, when it was combined with AM-112 at a 1:1 ratio. AM-112 demonstrates potential as a new beta-lactamase inhibitor.
authors.affiliation: Life and Health Sciences, Aston University, Birmingham. Micron Research, Cambridge, United Kingdom. conor.jamieson@swbh.nhs.uk
authors.forename: Conor E
authors.initials: CE
authors.lastname: Jamieson
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lambert
authors.forename: Iain N
authors.initials: IN
authors.lastname: Simpson
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000188:drug therapy; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002511:Cephalosporins / Q000494:pharmacology; D004359:Drug Therapy, Combination / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006602:Hexosyltransferases; D007769:Lactams; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C476288:(1'R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate; D001426:Bacterial Proteins; D002352:Carrier Proteins; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D007769:Lactams; D046915:Penicillin-Binding Proteins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase