RU 29 246, the active compound of the cephalosporin-prodrug-ester HR 916. II. Stability to beta-lactamases and affinity for penicillin-binding proteins

J Antibiot (Tokyo). 1992 Apr;45(4):521-6. doi: 10.7164/antibiotics.45.521.

Abstract

The aminothiazolyl-cephalosporin RU 29 246, the active metabolite of the prodrug-ester HR 916, is active against strains producing the widespread plasmid-encoded TEM-1, TEM-2 and SHV-1 beta-lactamases. Except for TEM-7 the activity of RU 29 246 against strains producing extended broad spectrum beta-lactamases (TEM-3, TEM-5, TEM-6, SHV-2, SHV-4, SHV-5, CMY-1, CTX-M), however, is low. Relative hydrolysis rates of RU 29 246 are comparable with those of cefpodoxime, the active metabolite of CS-807, and are extremely low for the TEM-1 and SHV-1 beta-lactamases. The compound demonstrates remarkable inhibitory activity against the chromosomal beta-lactamase of Enterobacter cloacae P99. In the presence of 1.7 microM this enzyme loses 50% of its activity. At concentrations of 0.43, 0.003 and 0.01 micrograms/ml the compound binds preferentially to the penicillin-binding protein (PBP) 3 of Escherichia coli K12, to the PBPs 2x and 3 of Streptococcus pneumoniae R6 and to PBP 1 of Staphylococcus aureus SG 511, respectively.

Publication types

  • Comparative Study

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins*
  • Binding, Competitive
  • Carrier Proteins / metabolism*
  • Cephalosporins / metabolism
  • Cephalosporins / pharmacology*
  • Drug Stability
  • Gram-Negative Bacteria / drug effects
  • Gram-Negative Bacteria / enzymology
  • Hexosyltransferases*
  • Microbial Sensitivity Tests
  • Muramoylpentapeptide Carboxypeptidase / metabolism*
  • Penicillin-Binding Proteins
  • Penicillins / metabolism*
  • Peptidyl Transferases*
  • Plasmids
  • Prodrugs / pharmacology*
  • beta-Lactamases / metabolism*

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Carrier Proteins
  • Cephalosporins
  • Penicillin-Binding Proteins
  • Penicillins
  • Prodrugs
  • RU 29246
  • Peptidyl Transferases
  • Hexosyltransferases
  • Muramoylpentapeptide Carboxypeptidase
  • beta-Lactamases