RU 29 246, the active compound of the cephalosporin-prodrug-ester HR 916. II. Stability to beta-lactamases and affinity for penicillin-binding proteins.
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.
Markus
A
A
Hoechst AG, Frankfurt/Main, Germany.
Klesel
N
N
Wollmann
T
T
Isert
D
D
Limbert
M
M
Schrinner
E
E
Seibert
G
G
Bauernfeind
A
A
Jungwirth
R
R
Wilhelm
R
R
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D002511:Cephalosporins / Q000378:metabolism / Q000494:pharmacology*; D004355:Drug Stability; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology; D006602:Hexosyltransferases; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism*; D046915:Penicillin-Binding Proteins; D010406:Penicillins / Q000378:metabolism*; D010458:Peptidyl Transferases; D010957:Plasmids; D011355:Prodrugs / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D002511:Cephalosporins; D046915:Penicillin-Binding Proteins; D010406:Penicillins; D011355:Prodrugs; C073743:RU 29246; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases