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. 1992 Apr;36(4):840–850. doi: 10.1128/aac.36.4.840

Iron transport-mediated antibacterial activity of and development of resistance to hydroxamate and catechol siderophore-carbacephalosporin conjugates.

A A Minnick 1, J A McKee 1, E K Dolence 1, M J Miller 1
PMCID: PMC189448  PMID: 1503447

Abstract

Peptides containing residues of N5-acetyl-N5-hydroxy-L-ornithine were evaluated as potential artificial siderophores of beta-lactam-hypersusceptible Escherichia coli X580. Only those peptides which were capable of forming a hexadentate complex around ferric iron, which is analogous to the natural siderophore ferrichrome, were able to reverse the growth inhibition effects of the ferric iron chelator ethylenediamine di(o-hydroxyphenylacetic acid). A synthetic bis(catechol) spermidine derivative, similar to the natural siderophores enterobactin and agrobactin, also exhibited siderophore activity with this strain. Conjugation of the N5-acetyl-N5-hydroxy-L-ornithine tripeptide and the bis(catechol) siderophore to the potent carbacephalosporin loracarbef and closely related analogs provided compounds which exhibited antibacterial activity against E. coli X580. As was observed with the naturally occurring albomycins, the initial bactericidal effect was followed by the appearance of survivors that were resistant to the test compound. An enhanced killing effect was observed when the parent was incubated simultaneously with hydroxamate and catechol siderophore-antibiotic conjugates. Natural and synthetic siderophore growth promotion experiments with survivors resistant to the conjugates strongly suggested that disabled ferrichrome and enterobactin-catechol assimilation mechanisms may be responsible for the observed resistance. One isolated survivor was postulated to be a tonB mutant. The antibacterial activities of the described siderophore-carbacephalosporin conjugates appear to be related to an iron transport assimilation mechanism and would not have been detected during routine MIC testing procedures.

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Selected References

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  1. Barbachyn M. R., Tuominen T. C. Synthesis and structure-activity relationships of monocarbams leading to U-78608. J Antibiot (Tokyo) 1990 Sep;43(9):1199–1203. doi: 10.7164/antibiotics.43.1199. [DOI] [PubMed] [Google Scholar]
  2. Basker M. J., Branch C. L., Finch S. C., Guest A. W., Milner P. H., Pearson M. J., Ponsford R. J., Smale T. C. Studies on semi-synthetic 7 alpha-formamidocephalosporins. I. Structure-activity relationships in some semi-synthetic 7 alpha-formamidocephalosporins. J Antibiot (Tokyo) 1986 Dec;39(12):1788–1791. doi: 10.7164/antibiotics.39.1788. [DOI] [PubMed] [Google Scholar]
  3. Basker M. J., Frydrych C. H., Harrington F. P., Milner P. H. Antibacterial activity of catecholic piperacillin analogues. J Antibiot (Tokyo) 1989 Aug;42(8):1328–1330. doi: 10.7164/antibiotics.42.1328. [DOI] [PubMed] [Google Scholar]
  4. Braun V., Günthner K., Hantke K., Zimmermann L. Intracellular activation of albomycin in Escherichia coli and Salmonella typhimurium. J Bacteriol. 1983 Oct;156(1):308–315. doi: 10.1128/jb.156.1.308-315.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Burton G., Best D. J., Dixon R. A., Kenyon R. F., Lashford A. G. Studies on 6 alpha-substituted penicillins. II. Synthesis and structure-activity relationships of 6 beta-(2-aryl-2-sulfoacetamido)-6 alpha-methoxy penicillanic acids. J Antibiot (Tokyo) 1986 Oct;39(10):1419–1429. doi: 10.7164/antibiotics.39.1419. [DOI] [PubMed] [Google Scholar]
  6. Chopra I., Ball P. Transport of antibiotics into bacteria. Adv Microb Physiol. 1982;23:183–240. doi: 10.1016/s0065-2911(08)60338-0. [DOI] [PubMed] [Google Scholar]
  7. Cox C. D. Effect of pyochelin on the virulence of Pseudomonas aeruginosa. Infect Immun. 1982 Apr;36(1):17–23. doi: 10.1128/iai.36.1.17-23.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Curtis N. A., Eisenstadt R. L., East S. J., Cornford R. J., Walker L. A., White A. J. Iron-regulated outer membrane proteins of Escherichia coli K-12 and mechanism of action of catechol-substituted cephalosporins. Antimicrob Agents Chemother. 1988 Dec;32(12):1879–1886. doi: 10.1128/aac.32.12.1879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dolence E. K., Lin C. E., Miller M. J., Payne S. M. Synthesis and siderophore activity of albomycin-like peptides derived from N5-acetyl-N5-hydroxy-L-ornithine. J Med Chem. 1991 Mar;34(3):956–968. doi: 10.1021/jm00107a013. [DOI] [PubMed] [Google Scholar]
  10. Dolence E. K., Minnick A. A., Lin C. E., Miller M. J., Payne S. M. Synthesis and siderophore and antibacterial activity of N5-acetyl-N5-hydroxy-L-ornithine-derived siderophore-beta-lactam conjugates: iron-transport-mediated drug delivery. J Med Chem. 1991 Mar;34(3):968–978. doi: 10.1021/jm00107a014. [DOI] [PubMed] [Google Scholar]
  11. Dolence E. K., Minnick A. A., Miller M. J. N5-acetyl-N5-hydroxy-L-ornithine-derived siderophore-carbacephalosporin beta-lactam conjugates: iron transport mediated drug delivery. J Med Chem. 1990 Feb;33(2):461–464. doi: 10.1021/jm00164a001. [DOI] [PubMed] [Google Scholar]
  12. Frost G. E., Rosenberg H. Relationship between the tonB locus and iron transport in Escherichia coli. J Bacteriol. 1975 Nov;124(2):704–712. doi: 10.1128/jb.124.2.704-712.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Griffiths G. L., Sigel S. P., Payne S. M., Neilands J. B. Vibriobactin, a siderophore from Vibrio cholerae. J Biol Chem. 1984 Jan 10;259(1):383–385. [PubMed] [Google Scholar]
  14. Hancock R. E., Hantke K., Braun V. Iron transport in Escherichia coli K-12. 2,3-Dihydroxybenzoate-promoted iron uptake. Arch Microbiol. 1977 Sep 28;114(3):231–239. doi: 10.1007/BF00446867. [DOI] [PubMed] [Google Scholar]
  15. Hantke K., Braun V. Membrane receptor dependent iron transport in Escherichia coli. FEBS Lett. 1975 Jan 1;49(3):301–305. doi: 10.1016/0014-5793(75)80771-x. [DOI] [PubMed] [Google Scholar]
  16. Harrington F. P., Knott S. J., O'Hanlon P. J., Southgate R. Structure-activity relationships in a series of piperazine-2,3-dione containing penicillins and cephalosporins. II. Derivatives substituted at N(4) of the piperazine ring. J Antibiot (Tokyo) 1989 Aug;42(8):1241–1247. doi: 10.7164/antibiotics.42.1241. [DOI] [PubMed] [Google Scholar]
  17. Hartmann A., Fiedler H. P., Braun V. Uptake and conversion of the antibiotic albomycin by Escherichia coli K-12. Eur J Biochem. 1979 Sep;99(3):517–524. doi: 10.1111/j.1432-1033.1979.tb13283.x. [DOI] [PubMed] [Google Scholar]
  18. Hollifield W. C., Jr, Neilands J. B. Ferric enterobactin transport system in Escherichia coli K-12. Extraction, assay, and specificity of the outer membrane receptor. Biochemistry. 1978 May 16;17(10):1922–1928. doi: 10.1021/bi00603a019. [DOI] [PubMed] [Google Scholar]
  19. Iwamatsu K., Atsumi K., Sakagami K., Ogino H., Yoshida T., Tsuruoka T., Shibahara S., Inouye S., Kondo S. A new antipseudomonal cephalosporin CP6162 and its congeners. J Antibiot (Tokyo) 1990 Nov;43(11):1450–1463. doi: 10.7164/antibiotics.43.1450. [DOI] [PubMed] [Google Scholar]
  20. Katsu K., Kitoh K., Inoue M., Mitsuhashi S. In vitro antibacterial activity of E-0702, a new semisynthetic cephalosporin. Antimicrob Agents Chemother. 1982 Aug;22(2):181–185. doi: 10.1128/aac.22.2.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Matsukuma I., Yoshiiye S., Mochida K., Hashimoto Y., Sato K., Okachi R., Hirata T. Synthesis and biological evaluation of 3-chloro-1-carbacephem compounds. Chem Pharm Bull (Tokyo) 1989 May;37(5):1239–1244. doi: 10.1248/cpb.37.1239. [DOI] [PubMed] [Google Scholar]
  22. McKee J. A., Sharma S. K., Miller M. J. Iron transport mediated drug delivery systems: synthesis and antibacterial activity of spermidine- and lysine-based siderophore-beta-lactam conjugates. Bioconjug Chem. 1991 Jul-Aug;2(4):281–291. doi: 10.1021/bc00010a013. [DOI] [PubMed] [Google Scholar]
  23. Miles A. A., Khimji P. L. Enterobacterial chelators of iron: their occurrence, detection, and relation to pathogenicity. J Med Microbiol. 1975 Nov;8(4):477–490. doi: 10.1099/00222615-8-4-477. [DOI] [PubMed] [Google Scholar]
  24. Mochida K., Ono Y., Yamasaki M., Shiraki C., Hirata T., Sato K., Okachi R. Aminothiazolylglycyl derivatives of carbacephem antibiotics. II. Synthesis and antibacterial activity of novel aminothiazolyl cephem compounds with hydroxypyridone moiety. J Antibiot (Tokyo) 1987 Feb;40(2):182–189. doi: 10.7164/antibiotics.40.182. [DOI] [PubMed] [Google Scholar]
  25. Mochida K., Shiraki C., Yamasaki M., Hirata T., Sato K., Okachi R. Aminothiazolylglycyl derivatives of carbacephems. I. Synthesis and antibacterial activity of novel carbacephems with substituted aminothiazolyl groups. J Antibiot (Tokyo) 1987 Jan;40(1):14–21. doi: 10.7164/antibiotics.40.14. [DOI] [PubMed] [Google Scholar]
  26. Mochizuki H., Oikawa Y., Yamada H., Kusakabe S., Shiihara T., Murakami K., Kato K., Ishiguro J., Kosuzume H. Antibacterial and pharmacokinetic properties of M14659, a new injectable semisynthetic cephalosporin. J Antibiot (Tokyo) 1988 Mar;41(3):377–391. doi: 10.7164/antibiotics.41.377. [DOI] [PubMed] [Google Scholar]
  27. Mochizuki H., Yamada H., Oikawa Y., Murakami K., Ishiguro J., Kosuzume H., Aizawa N., Mochida E. Bactericidal activity of M14659 enhanced in low-iron environments. Antimicrob Agents Chemother. 1988 Nov;32(11):1648–1654. doi: 10.1128/aac.32.11.1648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nakagawa S., Sanada M., Matsuda K., Hashizume T., Asahi Y., Ushijima R., Ohtake N., Tanaka N. In vitro and in vivo antibacterial activities of BO-1341, a new antipseudomonal cephalosporin. Antimicrob Agents Chemother. 1989 Sep;33(9):1423–1427. doi: 10.1128/aac.33.9.1423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nakagawa S., Sanada M., Matsuda K., Hazumi N., Tanaka N. Biological activity of BO-1236, a new antipseudomonal cephalosporin. Antimicrob Agents Chemother. 1987 Jul;31(7):1100–1105. doi: 10.1128/aac.31.7.1100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nikaido H., Rosenberg E. Y. Cir and Fiu proteins in the outer membrane of Escherichia coli catalyze transport of monomeric catechols: study with beta-lactam antibiotics containing catechol and analogous groups. J Bacteriol. 1990 Mar;172(3):1361–1367. doi: 10.1128/jb.172.3.1361-1367.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ogasa T., Saito H., Hashimoto Y., Sato K., Hirata T. Synthesis and biological evaluation of optically active 3-H-1-carbacephem compounds. Chem Pharm Bull (Tokyo) 1989 Feb;37(2):315–321. doi: 10.1248/cpb.37.315. [DOI] [PubMed] [Google Scholar]
  32. Ogino H., Iwamatsu K., Katano K., Nakabayashi S., Yoshida T., Shibahara S., Tsuruoka T., Inouye S., Kondo S. New aminothiazolylglycylcephalosporins with a 1,5-dihydroxy-4-pyridone-2-carbonyl group. II. Synthesis and antibacterial activity of MT0703 and its diastereomers. J Antibiot (Tokyo) 1990 Feb;43(2):189–198. doi: 10.7164/antibiotics.43.189. [DOI] [PubMed] [Google Scholar]
  33. Ohi N., Aoki B., Moro K., Kuroki T., Sugimura N., Noto T., Nehashi T., Matsumoto M., Okazaki H., Matsunaga I. Semisynthetic beta-lactam antibiotics. II. Effect on antibacterial activity of ureido N-substituents in the 6-[(R)-2-[3-(3,4-dihydroxybenzoyl)-1- ureido]-2-phenylacetamido]penicillanic acids. J Antibiot (Tokyo) 1986 Feb;39(2):242–250. doi: 10.7164/antibiotics.39.242. [DOI] [PubMed] [Google Scholar]
  34. Ohi N., Aoki B., Shinozaki T., Moro K., Kuroki T., Noto T., Nehashi T., Matsumoto M., Okazaki H., Matsunaga I. Semisynthetic beta-lactam antibiotics. IV. Synthesis and antibacterial activity of new ureidocephalosporin and ureidocephamycin derivatives containing a catechol moiety or its acetate. Chem Pharm Bull (Tokyo) 1987 May;35(5):1903–1909. [PubMed] [Google Scholar]
  35. Ohi N., Aoki B., Shinozaki T., Moro K., Noto T., Nehashi T., Okazaki H., Matsunaga I. Semisynthetic beta-lactam antibiotics. I. Synthesis and antibacterial activity of new ureidopenicillin derivatives having catechol moieties. J Antibiot (Tokyo) 1986 Feb;39(2):230–241. doi: 10.7164/antibiotics.39.230. [DOI] [PubMed] [Google Scholar]
  36. Ong S. A., Peterson T., Neilands J. B. Agrobactin, a siderophore from Agrobacterium tumefaciens. J Biol Chem. 1979 Mar 25;254(6):1860–1865. [PubMed] [Google Scholar]
  37. Payne S. M. Iron and virulence in the family Enterobacteriaceae. Crit Rev Microbiol. 1988;16(2):81–111. doi: 10.3109/10408418809104468. [DOI] [PubMed] [Google Scholar]
  38. Payne S. M. Synthesis and utilization of siderophores by Shigella flexneri. J Bacteriol. 1980 Sep;143(3):1420–1424. doi: 10.1128/jb.143.3.1420-1424.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Postle K., Skare J. T. Escherichia coli TonB protein is exported from the cytoplasm without proteolytic cleavage of its amino terminus. J Biol Chem. 1988 Aug 5;263(22):11000–11007. [PubMed] [Google Scholar]
  40. Rogers H. J. Iron-Binding Catechols and Virulence in Escherichia coli. Infect Immun. 1973 Mar;7(3):445–456. doi: 10.1128/iai.7.3.445-456.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Silley P., Griffiths J. W., Monsey D., Harris A. M. Mode of action of GR69153, a novel catechol-substituted cephalosporin, and its interaction with the tonB-dependent iron transport system. Antimicrob Agents Chemother. 1990 Sep;34(9):1806–1808. doi: 10.1128/aac.34.9.1806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sriyosachati S., Cox C. D. Siderophore-mediated iron acquisition from transferrin by Pseudomonas aeruginosa. Infect Immun. 1986 Jun;52(3):885–891. doi: 10.1128/iai.52.3.885-891.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tait G. H. The identification and biosynthesis of siderochromes formed by Micrococcus denitrificans. Biochem J. 1975 Jan;146(1):191–204. doi: 10.1042/bj1460191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wang C. C., Newton A. An additional step in the transport of iron defined by the tonB locus of Escherichia coli. J Biol Chem. 1971 Apr 10;246(7):2147–2151. [PubMed] [Google Scholar]
  45. Watanabe N. A., Nagasu T., Katsu K., Kitoh K. E-0702, a new cephalosporin, is incorporated into Escherichia coli cells via the tonB-dependent iron transport system. Antimicrob Agents Chemother. 1987 Apr;31(4):497–504. doi: 10.1128/aac.31.4.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wookey P. The tonB gene product in Escherichia coli. Energy-coupling or molecular processing of permeases? FEBS Lett. 1982 Mar 22;139(2):145–154. doi: 10.1016/0014-5793(82)80838-7. [DOI] [PubMed] [Google Scholar]

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