Overproduced beta-lactamase and the outer-membrane barrier as resistance factors in Serratia marcescens highly resistant to beta-lactamase-stable beta-lactam antibiotics

J Gen Microbiol. 1989 May;135(5):1275-90. doi: 10.1099/00221287-135-5-1275.

Abstract

In a clinical isolate of Serratia marcescens different states of low and high resistance to different beta-lactam antibiotics considered to be beta-lactamase-stable, viz. cefotaxime, ceftizoxime, ceftazidime, aztreonam, cefoxitin and imipenem, were found to be connected with the presence of constitutively overproduced, chromosomally encoded beta-lactamase at concentrations in the bacterial periplasm of 0.4 and 0.9 mM, respectively. All the antibiotics were degraded by the beta-lactamase. However, kinetic constants varied widely: k(m) from 92 to 0.012 microM and k(cat) from 3.4 to 2x10(-4)s(-1). The relative contributions to resistance by the functioning of periplasmic beta-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, ceftizomime, ceftazidime, aztreonam and latamoxef revealed overproduced beta-lactamase as the sole cause of the state of low resistance while antibiotic permeability was the same as in non-resistant S. marcescens strains. In contrast, high resistance was due to beta-lactamase action and decreased permeability of antibiotics. For resistance to aztreonam, only, immobilization of the antibiotic as covalent acyl-enzyme by newly synthesized beta-lactamase was essential. For cefoxitin, ampicillin and imipenem the analyses indicated that additional resistance factors may play a role, e.g. induction of beta-lactamase.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Aztreonam / pharmacology
  • Bacterial Proteins / biosynthesis*
  • Bacterial Proteins / genetics
  • Cell Membrane / metabolism
  • Cell Membrane Permeability
  • Drug Resistance, Microbial
  • Enterobacteriaceae Infections / drug therapy
  • Enterobacteriaceae Infections / microbiology
  • Enzyme Induction
  • Gene Expression Regulation, Bacterial*
  • Imipenem / pharmacology
  • Kinetics
  • Serratia marcescens / enzymology*
  • Serratia marcescens / genetics
  • Serratia marcescens / isolation & purification
  • beta-Lactamase Inhibitors
  • beta-Lactamases / biosynthesis*
  • beta-Lactamases / genetics

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • beta-Lactamase Inhibitors
  • Imipenem
  • beta-Lactamases
  • Aztreonam