Abstract
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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Selected References
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- Benz R., Hancock R. E. Properties of the large ion-permeable pores formed from protein F of Pseudomonas aeruginosa in lipid bilayer membranes. Biochim Biophys Acta. 1981 Aug 20;646(2):298–308. doi: 10.1016/0005-2736(81)90336-9. [DOI] [PubMed] [Google Scholar]
- Benz R., Janko K., Läuger P. Ionic selectivity of pores formed by the matrix protein (porin) of Escherichia coli. Biochim Biophys Acta. 1979 Mar 8;551(2):238–247. doi: 10.1016/0005-2736(89)90002-3. [DOI] [PubMed] [Google Scholar]
- Fukuoka T., Ohya S., Narita T., Katsuta M., Iijima M., Masuda N., Yasuda H., Trias J., Nikaido H. Activity of the carbapenem panipenem and role of the OprD (D2) protein in its diffusion through the Pseudomonas aeruginosa outer membrane. Antimicrob Agents Chemother. 1993 Feb;37(2):322–327. doi: 10.1128/aac.37.2.322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fung-Tomc J. C., Gradelski E., Kolek B., Minassian B., Pucci M., Kessler R. E., Bonner D. P. Activity of carbapenem BMS-181139 against Pseudomonas aeruginosa is not dependent on porin protein D2. Antimicrob Agents Chemother. 1995 Feb;39(2):386–393. doi: 10.1128/aac.39.2.386. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kitzis M. D., Acar J. F., Gutmann L. Antibacterial activity of meropenem against gram-negative bacteria with a permeability defect and against staphylococci. J Antimicrob Chemother. 1989 Sep;24 (Suppl A):125–132. doi: 10.1093/jac/24.suppl_a.125. [DOI] [PubMed] [Google Scholar]
- Sumita Y., Eguchi Y., Fukasawa M., Okuda T., Yamaga H., Matsumura H., Sunagawa M. The effect of 1 beta-methyl and imidoyl substituents on the antipseudomonal activity of carbapenems. J Antibiot (Tokyo) 1993 Oct;46(10):1629–1632. doi: 10.7164/antibiotics.46.1629. [DOI] [PubMed] [Google Scholar]
- Sumita Y., Fukasawa M., Okuda T. Comparison of two carbapenems, SM-7338 and imipenem: affinities for penicillin-binding proteins and morphological changes. J Antibiot (Tokyo) 1990 Mar;43(3):314–320. doi: 10.7164/antibiotics.43.314. [DOI] [PubMed] [Google Scholar]
- Trias J., Nikaido H. Protein D2 channel of the Pseudomonas aeruginosa outer membrane has a binding site for basic amino acids and peptides. J Biol Chem. 1990 Sep 15;265(26):15680–15684. [PubMed] [Google Scholar]
- Yoshihara E., Nakae T. Identification of porins in the outer membrane of Pseudomonas aeruginosa that form small diffusion pores. J Biol Chem. 1989 Apr 15;264(11):6297–6301. [PubMed] [Google Scholar]
- Yoshimura F., Nikaido H. Diffusion of beta-lactam antibiotics through the porin channels of Escherichia coli K-12. Antimicrob Agents Chemother. 1985 Jan;27(1):84–92. doi: 10.1128/aac.27.1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]