Structure-activity relationships on the terminal D-amino acid moiety of a novel cephamycin MT-141.
The effect of chemical modification of the D-amino acid function, which represents the C-7 beta substituent of cephamycin MT-141 on in vitro antibacterial activity was examined. MT-141 was more active on Gram-negative organisms than Gram-positive ones. It showed strong bacteriolytic activity on Gram-negative organisms. Lysis of Escherichia coli K-12 strain JE1011 treated with a low concentration of this antibiotic was preceded by frequent formation of multiple bulges from the cells. Amidation or decarboxylation, removing the acidic function from the D-amino acid of MT-141, resulted in an increase in activity against Gram-positive bacteria, and a decrease against Gram-negative ones. Cells treated with the amide or the decarboxylate did not form multiple bulges but formed single bulges. N-Acetylation of the D-amino acid moiety removing the basic function, caused a marked drop in activity against both Gram-positive and Gram-negative bacteria. The bacteriolytic activity on E. coli was reduced, and cells treated with the N-acetate became filamentous. Conversion of the D-amino acid function of MT-141 to the L configuration caused a moderate drop in activity against both Gram-positive and Gram-negative organisms. Both bacteriolytic and bactericidal activities against E. coli were reduced in the L-congener. Cefoxitin, cefmetazole and latamoxef used as reference antibiotics were less active than MT-141 in the bactericidal activity against E. coli, and induced single bulge formation or filamentation of the cells around MIC levels. Cell-surface permeability, stability to beta-lactamases, and binding affinity to PBPs of E. coli did not differ between MT-141 and its derivatives.
D001419:Bacteria / Q000187:drug effects; D001426:Bacterial Proteins; D001433:Bacteriolysis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002513:Cephamycins / Q000378:metabolism / Q000494:pharmacology*; D004492:Edetic Acid / Q000494:pharmacology; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000494:pharmacology
D001426:Bacterial Proteins; D002352:Carrier Proteins; D002513:Cephamycins; D046915:Penicillin-Binding Proteins; D004492:Edetic Acid; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases; C046079:cefminox