The effect of 1.BETA.-methyl and imidoyl substituents on the antipseudomonal activity of carbapenems.

Sumita, Yoshihiro; Eguchi, Yawara; Fukasawa, Masatomo; Okuda, Takuo; Yamaga, Hiroshi; Matsumura, Hideaki; Sunagawa, Makoto

doi:10.7164/antibiotics.46.1629

Cited by 12 publications

(4 citation statements)

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“…With meropenem, lower concentrations of the compound were required to induce filament formation than for bulge or spherical cell formation (this study and reference 9). Our PBP binding results indicated that meropenem does bind with slightly higher affinity to PBP-3 of P. aeruginosa than to PBP-2, confirming previous reports (5,8). Thus, filamentation (by inhibition of PBP-3) occurs in P. aeruginosa when the meropenem concentration is limited, but as the meropenem levels increase, PBP-2 is inactivated, with resulting spherical and bulge cell formation.…”

Section: Discussionsupporting

confidence: 79%

Structure-activity relationships of carbapenems that determine their dependence on porin protein D2 for activity against Pseudomonas aeruginosa

Fung‐Tomc

Huczko

Banville

et al. 1995

Antimicrob Agents Chemother

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A number of carbapenem derivatives were examined to determine the structure-activity relationships required for dependence on porin protein D2 for activity against Pseudomonas aeruginosa. As suggested by J. Trias and H. Nikaido (Antimicrob. Agents Chemother. 34:52-57, 1990), carbapenem derivatives, such as imipenem and meropenem, containing a sole basic group at position 2 of the molecule utilize the D2 channel for permeation through the outer membrane of pseudomonads; they are more active against D2-sufficient strains of P. aeruginosa. Our results indicated that carbapenems with a basic group at position 1 or 6 of the molecule did not depend on the D2 channel for activity; i.e., they were equally active against D2-sufficient and D2-deficient pseudomonal strains. However, addition of a basic group at position 1 or 6 of a carbapenem derivative already containing a basic group at position 2 resulted in its lack of dependency on the D2 pathway.Comparison between meropenem and its 1-guanidinoethyl derivative, BMY 45047, indicated that they differed in their dependence on D2; while meropenem required the D2 channel for uptake, BMY 45047 activity was independent of D2. Meropenem and BMY 45047 had similar affinities for the penicillin-binding proteins of P. aeruginosa. However, BMY 45047 and meropenem differed in the morphological changes that they induced in pseudomonal cells. While meropenem induced filamentation, BMY 45047 induced filaments only in BMS-181139-resistant mutants and not in imipenem-resistant mutants or in carbapenem-susceptible P. aeruginosa strains. These results suggested that in Mueller-Hinton medium the uptake of BMY 45047 through the non-D2 pathway is more rapid than that of meropenem through the D2 porin. In summary, the presence of a basic group at position 2 of a carbapenem is important for its preferential uptake by the D2 channel. However, the addition of a basic group at position 1 or 6 of a carbapenem already containing a basic group at position 2 dissociates its necessity for porin protein D2 for activity.

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Section: Discussionsupporting

confidence: 79%

Structure-activity relationships of carbapenems that determine their dependence on porin protein D2 for activity against Pseudomonas aeruginosa

Fung‐Tomc

Huczko

Banville

et al. 1995

Antimicrob Agents Chemother

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“…It is easy to imagine that this property varies with chemical structures. We previously studied antipseudomonal activi ties of carbapenems in terms of structureactivity relationships [33], The marked differ ence in the structure between meropenem and imipenem is that meropenem has a lß-methyl moiety on the carbapenem skeleton, and our results showed this substituent to affect the activity of carbapenems against P. aeruginosa [34], For example, with the introduction of a lß-methyl group onto imipenem and panipenem, the activities of these compounds were affected by the mpmB mutation. How ever, mpmB also influenced the activity of desmethyl meropenem.…”

Section: Discussionmentioning

confidence: 90%

Meropenem Resistance in <i>Pseudomonas aeruginosa</i>

Sumita

Fukasawa

1996

Chemotherapy

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Two genetically distinct classes of meropenem-low-susceptibility Pseudomonas oaeruginosa PA02152 mutants, which arose spontaneously, were isolated. Two meropenem resistance genes, mpmA and mpmB, were mapped near ilvB/C and proC, respectively, on the P. aeruginosa PAO chromosome. The mpmA was thought to be identical to oprD2 because of the cross-resistance to carbapenems and the association with the loss of the outer membrane protein D2 (OprD2). The mpmB mutation conferred a 4-fold increase in resistance to meropenem, and cross-resistance to various types of antimicrobial agents, e.g. carbenicillin, norfloxacin and chloramphenicol. However, the mpmB mutant was susceptible to imipenem. This mutant still possessed OprD2 and showed increased expression of a 48-kD outer membrane protein, although its profiles of Β-lactamase activity and affinities of penicillin-binding proteins for Β-lactams were indistinguishable from those of the parent strain. The resistance gene mpmB was considered to be an allele of nalB (or cfxB or oprK) from the results of the transductional analysis. The mutation frequency of mpmA:mpmB was in the ratio of 4:1. The same results were obtained in another clinically isolated P. aeruginosa strain. Meropenem resistance caused by both mpmA and mpmB mutations seemed to be due to the reduction in permeability of antibiotics through the outer membrane. These findings suggest a new pathway for the translocation of meropenem other than that mediated by OprD2 across the outer membrane. Thus, meropenem showed about 4- to 8-fold higher activity than imipenem against OprD2-deficient P. aeruginosa.

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“…The final reasons for the greater effect of meropenem than that of imipenem are not clear. However, taking into consideration the finding that meropenem exhibits higher affinity for all PBPs except PBP-1A in P. aeruginosa than imipenem, 31 its enhanced PALE may be related to phenotypic modifications with changes on the bacterial cell surface, causing bacteria to be more susceptible to phagocytic killing.…”

Section: Discussionmentioning

confidence: 96%

Pretreatment of Pseudomonas aeruginosa with a sub-MIC of imipenem enhances bactericidal activity of neutrophils

Sasahara

Satoh

Sekiguchi

et al. 2003

Journal of Infection and Chemotherapy

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The effect of 1.BETA.-methyl and imidoyl substituents on the antipseudomonal activity of carbapenems.

Abstract: Amongthe manyclinical pathogens Pseudomonas aeruginosa is understood as the bacterium that causes opportunistic infections in patients under immunosuppressed conditions or with cystic fibrosis or diffuse panbronchiolitis.

Cited by 12 publications

References 0 publications

Structure-activity relationships of carbapenems that determine their dependence on porin protein D2 for activity against Pseudomonas aeruginosa

Structure-activity relationships of carbapenems that determine their dependence on porin protein D2 for activity against Pseudomonas aeruginosa

Meropenem Resistance in <i>Pseudomonas aeruginosa</i>

Pretreatment of Pseudomonas aeruginosa with a sub-MIC of imipenem enhances bactericidal activity of neutrophils

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