In vitro and in vivo activities of AM-112, a novel oxapenem

Conor E. Jamieson*, Peter A. Lambert, Iain N. Simpson

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

AM-112[1′R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1′- hydroxyethyl)oxapenem-3-carboxylatel is a novel oxapenem compound which possesses potent β-lactamase-inhibitory properties. Fifty-percent inhibitory concentrations (IC50s) of AM-112 for class A enzymes were between 0.16 and 2.24 μM for three enzymes, compared to IC50s of 0.008 to 0.12 μM 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 μg/ml. Ceftazidime was combined with AM-112 at 1:1 and 2:1 ratios in MIC determination studies against a panel of β-lactamase-producing organisms. These studies demonstrated that AM-112 was effective at protecting ceftazidime against extended-spectrum β-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 β-lactamase inhibitor.

Original languageEnglish
Pages (from-to)1652-1657
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume47
Issue number5
DOIs
Publication statusPublished - May 2003

Fingerprint

Ceftazidime
Enterobacter cloacae
Clavulanic Acid
Klebsiella pneumoniae
4 alpha-glucanotransferase
In Vitro Techniques
(1'R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate
Enzymes
Penicillin-Binding Proteins
Cefoperazone
Ceftriaxone
Sepsis
Body Weight
Escherichia coli

Keywords

  • AM-112 [(1′R
  • 5R
  • 6R)-3-(4-amino-1
  • 1-dimethyl-butyl)-6-(1′-hydroxyethyl)oxapenem-3-carboxylate]
  • oxapenem compound
  • β-lactamase-inhibitory properties
  • enzymes
  • clavulanic acid
  • ceftazidime
  • extended-spectrum β-lactamase-producing strains
  • β-lactamase inhibitor

Cite this

Jamieson, Conor E. ; Lambert, Peter A. ; Simpson, Iain N. / In vitro and in vivo activities of AM-112, a novel oxapenem. In: Antimicrobial Agents and Chemotherapy. 2003 ; Vol. 47, No. 5. pp. 1652-1657.
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In vitro and in vivo activities of AM-112, a novel oxapenem. / Jamieson, Conor E.; Lambert, Peter A.; Simpson, Iain N.

In: Antimicrobial Agents and Chemotherapy, Vol. 47, No. 5, 05.2003, p. 1652-1657.

Research output: Contribution to journalArticle

TY - JOUR

T1 - In vitro and in vivo activities of AM-112, a novel oxapenem

AU - Jamieson, Conor E.

AU - Lambert, Peter A.

AU - Simpson, Iain N.

PY - 2003/5

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N2 - AM-112[1′R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1′- hydroxyethyl)oxapenem-3-carboxylatel is a novel oxapenem compound which possesses potent β-lactamase-inhibitory properties. Fifty-percent inhibitory concentrations (IC50s) of AM-112 for class A enzymes were between 0.16 and 2.24 μM for three enzymes, compared to IC50s of 0.008 to 0.12 μM 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 μg/ml. Ceftazidime was combined with AM-112 at 1:1 and 2:1 ratios in MIC determination studies against a panel of β-lactamase-producing organisms. These studies demonstrated that AM-112 was effective at protecting ceftazidime against extended-spectrum β-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 β-lactamase inhibitor.

AB - AM-112[1′R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1′- hydroxyethyl)oxapenem-3-carboxylatel is a novel oxapenem compound which possesses potent β-lactamase-inhibitory properties. Fifty-percent inhibitory concentrations (IC50s) of AM-112 for class A enzymes were between 0.16 and 2.24 μM for three enzymes, compared to IC50s of 0.008 to 0.12 μM 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 μg/ml. Ceftazidime was combined with AM-112 at 1:1 and 2:1 ratios in MIC determination studies against a panel of β-lactamase-producing organisms. These studies demonstrated that AM-112 was effective at protecting ceftazidime against extended-spectrum β-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 β-lactamase inhibitor.

KW - AM-112 [(1′R

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KW - 1-dimethyl-butyl)-6-(1′-hydroxyethyl)oxapenem-3-carboxylate]

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