Cefcapene inactivates chromosome-encoded class C beta-lactamases.
The stability of cefcapene and cefpodoxime, oral antibacterial cephalosporins, toward different classes of beta-lactamases was evaluated. For the class A beta-lactamases, TEM-1, SHV-1, and NMC-A, only the steady-state kinetic parameter ( k(cat)/ Km) values were calculated (3100 - 1.1 x 10(7) M(-1) x s(-1)), because these enzymes have very high Km values for cefpodoxime and cefotaxime. As for class B beta-lactamases L1, IMP-1, and CcrA, in general, similar k(cat)/ Km values were obtained. However, regarding class C beta-lactamases from Enterobacter cloacae, Escherichia coli, Pseudomonas aeruginosa, and Citrobacter freundii, we found major differences in stability between the two compounds. Cefpodoxime acted as a good substrate for the class C beta-lactamases, except for the enzyme from E. cloacae; its k(cat) and Km values were successfully calculated ( k(cat)/ Km, 1.8 x 10(5) - 1.2 x 10(7) M(-1) x s(-1)). On the other hand, cefcapene acted as a poor substrate or an inactivator for class C beta-lactamases; its k(2)/ K value was successfully calculated (8.7 x 10(5) - 7.0 x 10(6) M(-1) x s(-1)). In addition, k(3) values were determined for beta-lactamases from P. aeruginosa (2.3 x 10(-2) x s(-1)) and C. freundii (2.1 x 10(-1) x s(-1)). Even though these values could be calculated, transient inactivation as an enzyme reactivation reaction for all these enzymes was observed. These findings suggest the potential of cephem compounds as inhibitors of class C beta-lactamases.
Alba
Jimena
J
Department of Microbiology, Yamanashi Medical University, Tamaho-cho, Yamanashi 490-3898, Japan.
Ishii
Yoshikazu
Y
Galleni
Moreno
M
Frère
Jean-Marie
JM
Ito
Masahiko
M
Yamaguchi
Keizo
K
D015296:Ceftizoxime / Q000031:analogs & derivatives* / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology*; D002876:Chromosomes, Bacterial; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000235:genetics; D000097623:Cefpodoxime
D015296:Ceftizoxime; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D000097623:Cefpodoxime; C425944:cefcapene pivoxil hydrochloride