Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1995 Feb;39(2):386–393. doi: 10.1128/aac.39.2.386

Activity of carbapenem BMS-181139 against Pseudomonas aeruginosa is not dependent on porin protein D2.

J C Fung-Tomc 1, E Gradelski 1, B Kolek 1, B Minassian 1, M Pucci 1, R E Kessler 1, D P Bonner 1
PMCID: PMC162548  PMID: 7726503

Abstract

The broad antipseudomonal spectrum of the carbapenem BMS-181139 includes clinical strains and laboratory mutants of Pseudomonas aeruginosa that are resistant to imipenem. Unlike other known carbapenems (meropenem, panipenem, biapenem, and BO-2727), which have reduced activity against imipenem-resistant strains of P. aeruginosa, BMS-181139 was equally active against imipenem-susceptible (D2-sufficient) and imipenem-resistant (D2-deficient) strains. Conversely, imipenem and meropenem activities were the same against the susceptible parental strains and their BMS-181139-resistant mutants. Whereas basic amino acids antagonized the antipseudomonal activities of imipenem and meropenem, they had no effect on the activity of BMS-181139. These results suggest that the uptake of BMS-181139 into pseudomonal cells occurs by a non-D2 pathway. Compared with imipenem and meropenem, BMS-181139 may have a slightly higher affinity for penicillin-binding protein 2 (PBP-2) of P. aeruginosa. The rates of resistance development to imipenem, meropenem, and BMS-181139 in P. aeruginosa strains were similar; resistance occurred at frequencies of approximately 10(-7) to 10(-8). Resistance to BMS-181139 in P. aeruginosa is presumed to be caused by its diminished permeability since no change in their penicillin-binding protein affinities or beta-lactamase levels could be detected. In summary, BMS-181139 is a new carbapenem which differs from other known carbapenems in its lack of cross-resistance with imipenem. This difference could be explained by the permeation of BMS-181139 through a non-D2 channel, compared to the preferential uptake of other carbapenems by the D2 porin.

Full Text

The Full Text of this article is available as a PDF (237.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Büscher K. H., Cullmann W., Dick W., Wendt S., Opferkuch W. Imipenem resistance in Pseudomonas aeruginosa is due to diminished expression of outer membrane proteins. J Infect Dis. 1987 Oct;156(4):681–684. doi: 10.1093/infdis/156.4.681. [DOI] [PubMed] [Google Scholar]
  2. Catchpole C. R., Wise R., Thornber D., Andrews J. M. In vitro activity of L-627, a new carbapenem. Antimicrob Agents Chemother. 1992 Sep;36(9):1928–1934. doi: 10.1128/aac.36.9.1928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Fung-Tomc J., Dougherty T. J., DeOrio F. J., Simich-Jacobson V., Kessler R. E. Activity of cefepime against ceftazidime- and cefotaxime-resistant gram-negative bacteria and its relationship to beta-lactamase levels. Antimicrob Agents Chemother. 1989 Apr;33(4):498–502. doi: 10.1128/aac.33.4.498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gaynes R. P., Culver D. H. Resistance to imipenem among selected gram-negative bacilli in the United States. Infect Control Hosp Epidemiol. 1992 Jan;13(1):10–14. doi: 10.1086/646417. [DOI] [PubMed] [Google Scholar]
  6. Godfrey A. J., Bryan L. E. Penetration of beta-lactams through Pseudomonas aeruginosa porin channels. Antimicrob Agents Chemother. 1987 Aug;31(8):1216–1221. doi: 10.1128/aac.31.8.1216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gotoh N., Nishino T. Decreases of the susceptibility to low molecular weight beta-lactam antibiotics in imipenem-resistant Pseudomonas aeruginosa mutants: role of outer membrane protein D2 in their diffusion. J Antimicrob Chemother. 1990 Feb;25(2):191–198. doi: 10.1093/jac/25.2.191. [DOI] [PubMed] [Google Scholar]
  8. Hancock R. E., Carey A. M. Outer membrane of Pseudomonas aeruginosa: heat- 2-mercaptoethanol-modifiable proteins. J Bacteriol. 1979 Dec;140(3):902–910. doi: 10.1128/jb.140.3.902-910.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hancock R. E., Nikaido H. Outer membranes of gram-negative bacteria. XIX. Isolation from Pseudomonas aeruginosa PAO1 and use in reconstitution and definition of the permeability barrier. J Bacteriol. 1978 Oct;136(1):381–390. doi: 10.1128/jb.136.1.381-390.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hopkins J. M., Towner K. J. Enhanced resistance to cefotaxime and imipenem associated with outer membrane protein alterations in Enterobacter aerogenes. J Antimicrob Chemother. 1990 Jan;25(1):49–55. doi: 10.1093/jac/25.1.49. [DOI] [PubMed] [Google Scholar]
  11. Huang H., Hancock R. E. Genetic definition of the substrate selectivity of outer membrane porin protein OprD of Pseudomonas aeruginosa. J Bacteriol. 1993 Dec;175(24):7793–7800. doi: 10.1128/jb.175.24.7793-7800.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kapotas N. M. Acclimatization resistance of a Pseudomonas aeruginosa prototype strain to imipenem. J Antibiot (Tokyo) 1991 Sep;44(9):985–994. doi: 10.7164/antibiotics.44.985. [DOI] [PubMed] [Google Scholar]
  13. Kessler R. E., Fung-Tomc J., Kolek B., Minassian B., Huczko E., Gradelski E., Bonner D. P. In vitro activity of BMS-181139, a new carbapenem with potent antipseudomonal activity. Antimicrob Agents Chemother. 1995 Feb;39(2):380–385. doi: 10.1128/aac.39.2.380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  16. Laemmli U. K., Favre M. Maturation of the head of bacteriophage T4. I. DNA packaging events. J Mol Biol. 1973 Nov 15;80(4):575–599. doi: 10.1016/0022-2836(73)90198-8. [DOI] [PubMed] [Google Scholar]
  17. Livermore D. M. Interplay of impermeability and chromosomal beta-lactamase activity in imipenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1992 Sep;36(9):2046–2048. doi: 10.1128/aac.36.9.2046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Livermore D. M., Yang Y. J. Beta-lactamase lability and inducer power of newer beta-lactam antibiotics in relation to their activity against beta-lactamase-inducibility mutants of Pseudomonas aeruginosa. J Infect Dis. 1987 Apr;155(4):775–782. doi: 10.1093/infdis/155.4.775. [DOI] [PubMed] [Google Scholar]
  19. Livermore D. M., Yang Y. J. Comparative activity of meropenem against Pseudomonas aeruginosa strains with well-characterized resistance mechanisms. J Antimicrob Chemother. 1989 Sep;24 (Suppl A):149–159. doi: 10.1093/jac/24.suppl_a.149. [DOI] [PubMed] [Google Scholar]
  20. Lynch M. J., Drusano G. L., Mobley H. L. Emergence of resistance to imipenem in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1987 Dec;31(12):1892–1896. doi: 10.1128/aac.31.12.1892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nakae T. Outer-membrane permeability of bacteria. Crit Rev Microbiol. 1986;13(1):1–62. doi: 10.3109/10408418609108734. [DOI] [PubMed] [Google Scholar]
  22. Nakagawa S., Hashizume T., Matsuda K., Sanada M., Okamoto O., Fukatsu H., Tanaka N. In vitro activity of a new carbapenem antibiotic, BO-2727, with potent antipseudomonal activity. Antimicrob Agents Chemother. 1993 Dec;37(12):2756–2759. doi: 10.1128/aac.37.12.2756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nicas T. I., Hancock R. E. Pseudomonas aeruginosa outer membrane permeability: isolation of a porin protein F-deficient mutant. J Bacteriol. 1983 Jan;153(1):281–285. doi: 10.1128/jb.153.1.281-285.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nikaido H. Porins and specific channels of bacterial outer membranes. Mol Microbiol. 1992 Feb;6(4):435–442. doi: 10.1111/j.1365-2958.1992.tb01487.x. [DOI] [PubMed] [Google Scholar]
  25. Nikaido H. Role of permeability barriers in resistance to beta-lactam antibiotics. Pharmacol Ther. 1985;27(2):197–231. doi: 10.1016/0163-7258(85)90069-5. [DOI] [PubMed] [Google Scholar]
  26. Piddock L. J., Traynor E. A. beta-Lactamase expression and outer membrane protein changes in cefpirome-resistant and ceftazidime-resistant gram-negative bacteria. J Antimicrob Chemother. 1991 Aug;28(2):209–219. doi: 10.1093/jac/28.2.209. [DOI] [PubMed] [Google Scholar]
  27. Piddock L. J., Turner H. L. Activity of meropenem against imipenem-resistant bacteria and selection in vitro of carbapenem-resistant Enterobacteriaceae. Eur J Clin Microbiol Infect Dis. 1992 Dec;11(12):1186–1191. doi: 10.1007/BF01961143. [DOI] [PubMed] [Google Scholar]
  28. Pucci M. J., Boice-Sowek J., Kessler R. E., Dougherty T. J. Comparison of cefepime, cefpirome, and cefaclidine binding affinities for penicillin-binding proteins in Escherichia coli K-12 and Pseudomonas aeruginosa SC8329. Antimicrob Agents Chemother. 1991 Nov;35(11):2312–2317. doi: 10.1128/aac.35.11.2312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Quinn J. P., Studemeister A. E., DiVincenzo C. A., Lerner S. A. Resistance to imipenem in Pseudomonas aeruginosa: clinical experience and biochemical mechanisms. Rev Infect Dis. 1988 Jul-Aug;10(4):892–898. doi: 10.1093/clinids/10.4.892. [DOI] [PubMed] [Google Scholar]
  30. Raimondi A., Traverso A., Nikaido H. Imipenem- and meropenem-resistant mutants of Enterobacter cloacae and Proteus rettgeri lack porins. Antimicrob Agents Chemother. 1991 Jun;35(6):1174–1180. doi: 10.1128/aac.35.6.1174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Satake S., Yoneyama H., Nakae T. Role of OmpD2 and chromosomal beta-lactamase in carbapenem resistance in clinical isolates of Pseudomonas aeruginosa. J Antimicrob Chemother. 1991 Aug;28(2):199–207. doi: 10.1093/jac/28.2.199. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Trias J., Dufresne J., Levesque R. C., Nikaido H. Decreased outer membrane permeability in imipenem-resistant mutants of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1989 Aug;33(8):1202–1206. doi: 10.1128/aac.33.8.1202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Trias J., Nikaido H. Outer membrane protein D2 catalyzes facilitated diffusion of carbapenems and penems through the outer membrane of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1990 Jan;34(1):52–57. doi: 10.1128/aac.34.1.52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. Voutsinas D., Mavroudis T., Avlamis A., Giamarellou H. In-vitro activity of meropenem, a new carbapenem, against multiresistant Pseudomonas aeruginosa compared with that of other antipseudomonal antimicrobials. J Antimicrob Chemother. 1989 Sep;24 (Suppl A):143–147. doi: 10.1093/jac/24.suppl_a.143. [DOI] [PubMed] [Google Scholar]
  37. Vurma-Rapp U., Kayser F. H., Hadorn K., Wiederkehr F. Mechanism of imipenem resistance acquired by three Pseudomonas aeruginosa strains during imipenem therapy. Eur J Clin Microbiol Infect Dis. 1990 Aug;9(8):580–587. doi: 10.1007/BF01967212. [DOI] [PubMed] [Google Scholar]
  38. Wiedemann B., Zühlsdorf M. Antibacterial properties of meropenem towards clinical isolates, beta-lactamase producers and laboratory mutants. J Antimicrob Chemother. 1989 Sep;24 (Suppl A):197–205. doi: 10.1093/jac/24.suppl_a.197. [DOI] [PubMed] [Google Scholar]
  39. Yang Y. J., Livermore D. M. Interactions of meropenem with class I chromosomal beta-lactamases. J Antimicrob Chemother. 1989 Sep;24 (Suppl A):207–217. doi: 10.1093/jac/24.suppl_a.207. [DOI] [PubMed] [Google Scholar]
  40. 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]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES