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.

Abstract

The anti-i/. influenzae activity of meropenem(la) was muchhigher than those of imipenem (4), panipenem (2b) and biapenem (7). To clarify the major structural features responsible for the anti-i/. influenzae activity of carbapenem compounds,the structure-activity relationship to the anti-//. influenzae activity was investigated. The anti-//. influenzae activities of meropenem(la) and l/?-methyl-panipenem (2a) were much higher than those ofdesmethyl-meropenem (lb) and panipenem (2b), respectively. Two carbapenems (5, 6) and imipenem (4), that have a strong basic C-2 side chain, showed lower anti-//. influenzae activity than meropenem(la) having a weakly basic C-2 side chain and iV-acetyl thienamycin (3) having a neutral C-2 side chain, respectively. As a result, we found that the introduction of the 1^-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. Haemophilus influenzae is an important pathogen that causes purulent meningitis in infants and severe infections in immunocompromisedadults1}. Meropenemis a carbapenemantibiotic that has been accepted for clinical use, and its potency against H. influenzae is markedly higher than those of other carbapenems such as imipenem and panipenem2~6). The anti-i/. influenzae activity of meropenemis equivalent to those of thirdgeneration cephems2'3'6), and sufficient for clinical use. Although imipenem-highly-resistant H. influenzae strains were isolated from clinical sources in recent years, meropenemhas maintained sufficient activity against clinical isolates3'5'6*, and meropenem-resistant H. influenzae

Antibacterial activity of carbapenems against clinically isolated respiratory bacterial pathogens in Japan between 2005 and 2006

“…Therefore, it is suggested that the antibacterial activity of the other carbapenems against H. influenzae may have further declined due to a recent increase in the number of BLNAR strains. Differences in the binding affinity of carbapenems to H. influenzae PBP3A and PBP3B are considered to play a role in the differences in their antibacterial activity against H. influenzae [14].…”

Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

“…Inhibition of the activity of high‐molecular weight PBPs (transpeptidases) results in abrogation of peptidoglycan crosslinking and is thought to ultimately contribute to the bactericidal activity of β‐lactams through loss of cell wall integrity . Additionally, different β‐lactams have differing affinities for the different types of PBP that a given bacteria may possess . Among the most clinically relevant gram‐negative bacteria, such as Escherichia coli and P. aeruginosa , imipenem generally exhibits the highest affinity for PBP 2, followed by 1a, 1b, and 3 …”

“…[33][34][35] Additionally, different β-lactams have differing affinities for the different types of PBP that a given bacteria may possess. [36][37][38][39] Among the most clinically relevant gram-negative bacteria, such as Escherichia coli and P. aeruginosa, imipenem generally exhibits the highest affinity for PBP 2, followed by 1a, 1b, and 3. 31,40 Relebactam β-Lactamases contribute to antimicrobial resistance by directly inactivating β-lactams through the catalyzing of the hydrolysis of the β-lactam ring, thus reducing the amount of active drug available for inhibition of PBP.…”

Antibacterial activity of carbapenems against clinical isolates of respiratory bacterial pathogens in the northeastern region of Japan in 2007

“…In contrast, MICs above the pneumonia breakpoint [7,8] were observed for the other carbapenems, mainly against the gBLNAR strains. Discrepancies in the susceptibility of H. influenzae to carbapenems are thought to be due to the differences in their binding affinities to H. influenzae PBP3A and PBP3B [18]. H. influenzae is the second most dominant pathogen responsible for CAP in Japan [15].…”