Sch 29482: Stability and inhibitory potency towards -lactamases from Gram-negative bacteria

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Abstract
Sch 29482 (SCH) has been exposed to fully characterized β -lactamases extracted from 32 different Gram-negative bacteria. The enzyme-substrate reactions were first observed in a spectrophotometer at 37°C for 1 h. The absorption spectrum of SCH, moxalactam and cefoxitin remained unchanged with all the β -lactamases tested, demonstrating the high stability of these three compounds. Additional measurements were done with a more sensitive microbiological assay over a 24-h period. All β -lactamase preparations inactivated cephaloridine. Cefoxitin and SCH lost some activity in 11 cases and moxalactam, the most stable of the three, in only 3 cases. Slow hydrolysis was not necessarily associated with high MIC's. After testing spectrophotometrically the 32 β -lactamases with nitrocefin as substrate, it appeared that SCH produced an inhibitory effect on most cephalosporinases. K i /K m values ranged from 10 −2 to 7 × l0 −3 i.e. good inhibition, for the β -lactamases found in Enterobacter cloacae P 99, Ent. aerogenes MULB 250, Citrobacter freundii MULB 601, Achromobacter xylosoxidans MULB 906 and Pseudomonas aeruginosa R 7. On the other hand, no or weak inhibition was observed with the β -lactamases of Acinetobacter calcoaceticus, Proteus vulgaris, Citrobacter divers us, Klebsiella oxytoca and most of the plasmid-mediated penicillinases. SCH is the only orally administrable β -lactam drug having such stability and inhibitory properties towards β -lactamases.