Structure-activity relationships of carbapenem compounds to anti-Haemophilus influenzae activity and affinity for penicillin-binding proteins. Effect of 1β-methyl group and C-2 side chain

Abstract

The anti-H. influenzae activity of meropenem (1a) was much higher than those of imipenem (4), panipenem (2b) and biapenem (7). To clarify the major structural features responsible for the anti-H. influenzae activity of carbapenem compounds, the structure-activity relationship to the anti-H. influenzae activity was investigated. The anti-H. influenzae activities of meropenem (1a) and 1β-methyl-panipenem (2a) were much higher than those of desmethyl-meropenem (1b) and panipenem (2b), respectively. Two carbapenems (5,6) and imipenem (4), that have a strong basic C-2 side chain, showed lower anti-H. influenzae activity than meropenem (1a) having a weakly basic C-2 side chain and N-acetyl thienamycin (3) having a neutral C-2 side chain, respectively. As a result, we found that the introduction of the 1a-methyl group or the reduction of the basicity (cationic character) of the C-2 side chain increased the antimicrobial activity and bactericidal activity of carbapenems against H. influenzae due to their increased affinity for PBP-4 and PBP-5.