Role of the 7 alpha-methoxy and side-chain carboxyl of moxalactam in beta-lactamase stability and antibacterial activity.
The effects of the alpha-carboxyl of the phenylmalonyl side chain and the 7 alpha-methoxy group in moxalactam (6059-S) (7 beta-[2-carboxy-2-(4-hydroxyphenyl) acetamido]-7 alpha-methoxy-3[[(1-methyl-1H-tetrazol-5-y])thio] methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid) and in the 1-sulfur congener on the stability to beta-lactamase were investigated by spectrophotometric and microbiological assays. The 7 alpha-methoxy substituent stabilized the compounds against penicillinase hydrolysis, and the alpha-carboxyl group stabilized them against cephalosporinase. An exception is the beta-lactamase produced by Proteus vulgaris, an inducible cephalosporinase, which hydrolyzed compounds having the alpha-carboxyl group but not those having the 7 alpha-methoxy group. Both substituents exerted their stabilizing effects independently, and compounds with both substituents, e.g., moxalactam (6059-S) and its 1-sulfur congener, were resistant to both penicillinases and cephalosporinases. The stabilization of the compounds to beta-lactamase hydrolysis improved their antibacterial activity against beta-lactamase-producing strains.
D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D002511:Cephalosporins / Q000378:metabolism*; D002513:Cephamycins / Q000378:metabolism*; D004355:Drug Stability; D006868:Hydrolysis; D008826:Microbial Sensitivity Tests; D009070:Moxalactam; D011514:Proteus vulgaris / Q000201:enzymology; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D002513:Cephamycins; D001618:beta-Lactamases; D009070:Moxalactam