Overproduced β-Lactamase and the Outer-membrane Barrier as Resistance Factors in Highly Resistant to β-Lactamase-stable β-Lactam Antibiotics Free

Abstract

In a clinical isolate of different states of low and high resistance to different β-lactam antibiotics considered to be -lactamase-stable, viz. cefotaxime, ceftizoxime, ceftazidime, aztreonam, cefoxitin and imipenem, were found to be connected with the presence of constitutively overproduced, chromosomally encoded -lactamase at concentrations in the bacterial periplasm of 0·4 and 0·9 m, respectively. All the antibiotics were degraded by the -lactamase. However, kinetic constants varied widely: from 92 to 0·012 µ, and from 3·4 to 2 × 10 s. The relative contributions to resistance by the functioning of periplasmic -lactamase, resynthesis of this enzyme, and limitation of antibiotic penetration by the bacterial outer membrane were analysed by computer simulations according to steady-state and non-steady-state models of interactions in the periplasm. Results for cefotaxime, ceftizoxime, ceftazidime, aztreonam and latamoxef revealed overproduced -lactamase as the sole cause of the state of low resistance while antibiotic permeability was the same as in non-resistant strains. In contrast, high resistance was due to -lactamase action and decreased permeability of antibiotics. For resistance to aztreonam, only, immobilization of the antibiotic as covalent acyl-enzyme by newly synthesized -lactamase was essential. For cefoxitin, ampicillin and imipenem the analyses indicated that additional resistance factors may play a role, e.g. induction of -lactamase.

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1989-05-01
2024-03-28
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