Role of the aminothiadiazolyl group in the antipseudomonal activity of cefclidin.
Cefclidin (E1040), which has an aminothiadiazolyl group in the 7 beta-side chain, showed about four-fold higher activity against Pseudomonas aeruginosa than its aminothiazolyl counterpart. Cefclidin had lower affinity and a higher Vmax value for the chromosomal type I beta-lactamase (cephalosporinase) from P. aeruginosa than its aminothiazolyl counterpart. No differences between the affinities of both compounds for the most of the sensitive essential PBPs were observed. Hydrophilicity of cefclidin was higher than that of its counterpart. The antipseudomonal activity of cefclidin, which was increased by the introduction of the aminothiadiazolyl group, was suggested to have resulted mainly from higher resistance to cephalosporinase hydrolysis at pharmacologically relevant low concentrations due to its low affinity for cephalosporinase, and secondarily from good penetration of cefclidin through the outer membrane due to increased hydrophilicity.
Watanabe
N
N
Department of Microbiology and Infectious Diseases, Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Sugiyama
I
I
D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002510:Cephalosporinase / Q000378:metabolism; D002511:Cephalosporins / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006602:Hexosyltransferases; D006868:Hydrolysis; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000494:pharmacology*; D047090:beta-Lactams / Q000378:metabolism
D001426:Bacterial Proteins; D002352:Carrier Proteins; D002511:Cephalosporins; D046915:Penicillin-Binding Proteins; D013830:Thiadiazoles; D047090:beta-Lactams; C056494:cefclidin; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D002510:Cephalosporinase