Abstract
A new β-lactamase inhibitor, SYN-1012, with a penem skeleton was synthesized and its biological activity compared with clavulanic acid, sulbactam, tazobactam and BRL-42715. The β-lactamase inhibitory activity of SYN-1012 was comparable to BRL-42715. Clavulanate and penam sulphones (sulbactam and tazobactam) were more active against TEM-1 and OXA-1, but were less active against TEM-3 and cephalosporinase (Case) than SYN-1012. In combination with piperacillin, SYN-1012 exhibited comparable or slightly lower synergistic effects than BRL-42715 against all the Gram-positive and Gram-negative isolates tested with only exception of Pseudomonas aeruginosa. The separate combinations of SYN-1012 and BRL-42715 with ceftazidime and cefotaxime provided comparable results against Gram-negatives, but not against Gram-positive isolates. Tazobactam was inferior to SYN-1012 in all cases. In comparison to tazobactam, SYN-1012 and BRL-42715 were relatively unstable in human and mouse plasma, and in mouse liver and kidney homogenates. Serum level of SYN-1012 and BRL-42715 after an intravenous administration of 20mg/kg in rabbit was undetectable after 1 hour.
