Carbapenems as inhibitors of OXA-13, a novel, integron-encoded beta-lactamase in Pseudomonas aeruginosa.
A clinical Pseudomonas aeruginosa strain, PAe391, was found to be resistant to a number of antibiotics including ticarcillin, piperacillin, cefsulodin and amikacin, and a disk diffusion assay showed evidence of pronounced synergy between imipenem and various beta-lactam antibiotics. Cloning and nucleotide sequence analysis revealed the dicistronic arrangement of an aac(6')-Ib variant and a novel blaOXA-type gene between the intI and qacE delta 1 genes typical of integrons, in PAe391, this integron was apparently chromosome-borne. The beta-lactamase, named OXA-13, displayed nine amino acid changes with respect to OXA-10:I in position 10 of OXA-10 to T (I10T), G20S, D55N, N73S, T107S, Y174F, E229G, S245N and E259A, OXA-13 (pIapp = 8.0) showed poor catalytic activity against penicillins as well as cephalosporins, but was efficient in hydrolysing some penicillinase-resistant beta-lactams, such as cefotaxime and aztreonam. It was efficiently inhibited by imipenem (KIapp = 11 nM), and formed a stable complex. While the KIapp value of meropenem was similar (16 nM), the corresponding complex was less stable.
Mugnier
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P
1 Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Paris VI, 15 rue de I'Ecole de Médecine, 75270 Paris Cedex 06, France.
Podglajen
I
I
1 Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Paris VI, 15 rue de I'Ecole de Médecine, 75270 Paris Cedex 06, France.
Goldstein
F W
FW
2 Service de Microbiologie Médicale, Fondation HoCpital Saint-Joseph, 7 rue Pierre-Larousse, 75674 Paris Cedex 14, France.
Collatz
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E
1 Laboratoire de Recherche Moléculaire sur les Antibiotiques, Université Paris VI, 15 rue de I'Ecole de Médecine, 75270 Paris Cedex 06, France.
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics; D001483:Base Sequence; D015780:Carbapenems / Q000494:pharmacology*; D002510:Cephalosporinase / Q000032:analysis* / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics; D004352:Drug Resistance, Microbial / Q000235:genetics; D005798:Genes, Bacterial / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D008969:Molecular Sequence Data; D010641:Phenotype; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D015780:Carbapenems; D065093:beta-Lactamase Inhibitors; D002510:Cephalosporinase; C112402:beta-lactamase OXA-13; D001618:beta-Lactamases