Structure-activity relationships of carbapenem compounds to anti-Haemophilus influenzae activity and affinity for penicillin-binding proteins. Effect of 1 beta-methyl group and C-2 side chain.
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 1 beta-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 1 beta-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.
Kanazawa
K
K
Sumitomo Pharmaceuticals Research Center, Osaka, Japan.
Nouda
H
H
Sunagawa
M
M
D000900:Anti-Bacterial Agents / Q000378:metabolism; D001426:Bacterial Proteins; D015780:Carbapenems / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism*; D006193:Haemophilus influenzae / Q000187:drug effects*; D006602:Hexosyltransferases; D015378:Imipenem / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000077731:Meropenem; D008745:Methylation; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism*; D046915:Penicillin-Binding Proteins; D010406:Penicillins / Q000378:metabolism*; D010458:Peptidyl Transferases; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013845:Thienamycins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D010406:Penicillins; D013845:Thienamycins; D015378:Imipenem; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D000077731:Meropenem; C039536:panipenem; C065257:biapenem