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. 1996 Nov;40(11):2610–2617. doi: 10.1128/aac.40.11.2610

Species selectivity of new siderophore-drug conjugates that use specific iron uptake for entry into bacteria.

M S Diarra 1, M C Lavoie 1, M Jacques 1, I Darwish 1, E K Dolence 1, J A Dolence 1, A Ghosh 1, M Ghosh 1, M J Miller 1, F Malouin 1
PMCID: PMC163585  PMID: 8913474

Abstract

Siderophores selectively bind ferric iron and are involved in receptor-specific iron transport into bacteria. Several types of siderophores were synthesized, and growth-promoting or inhibitory activities when they were conjugated to carbacephalosporin, erythromycylamine, or nalidixic acid were investigated. Overall, 11 types of siderophores and 21 drug conjugates were tested against seven different bacterial species: Escherichia coli, Bordetella bronchiseptica, Pasteurella multocida, Pasteurella haemolytica, Streptococcus suis, Staphylococcus aureus, and Staphylococcus epidermidis. In some species, the inhibitory activities of the drug conjugates were associated with the ability of the bacteria to use the siderophore portion of the molecules for growth promotion in disc diffusion tests (0.04 mumol of conjugate or siderophore per disc). E. coli used catechol-based siderophore portions as well as hydroxamate-based tri-delta-OH-N-OH-delta-N-acetyl-L-ornithine ferric iron ligands for growth under iron-restricted conditions achieved by supplemental ethylenediamine di (O-hydroxyphenylacetic acid) (100 micrograms/ml) and was sensitive to carbacephalosporin conjugated to these siderophore types (up to a 34-mm-diameter inhibition zone). B. bronchiseptica used desferrioxamine B and an isocyanurate-based or trihydroxamate in addition to catechol-based siderophore portions for promotion but was not inhibited by beta-lactam conjugates partly because of the presence of beta-lactamase. P. multocida and P. haemolytica did not use any of the synthetic siderophores for growth promotion, and the inhibitory activities of some conjugates seemed partly linked to their ability to withhold iron from these bacteria, since individual siderophore portions showed some antibacterial effects. Individual siderophores did not promote S. suis growth in restrictive conditions, but the type of ferric iron ligands attached to beta-lactams affected inhibitory activities. The antibacterial activities of the intracellular-acting agents erythromycylamine and nalidixic acid were reduced or lost, even against S. aureus and S. epidermidis, when the agents were conjugated to siderophores. Conjugate-resistant E. coli mutants showed the absence of some iron-regulated outer membrane proteins in gel electrophoresis profiles and in specific phage or colicin sensitivity tests, implying that the drugs used outer membrane receptors of ferric complexes to get into cells.

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Selected References

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  1. Abdullah K. M., Udoh E. A., Shewen P. E., Mellors A. A neutral glycoprotease of Pasteurella haemolytica A1 specifically cleaves O-sialoglycoproteins. Infect Immun. 1992 Jan;60(1):56–62. doi: 10.1128/iai.60.1.56-62.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arends J. P., Zanen H. C. Meningitis caused by Streptococcus suis in humans. Rev Infect Dis. 1988 Jan-Feb;10(1):131–137. doi: 10.1093/clinids/10.1.131. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Brochu A., Brochu N., Nicas T. I., Parr T. R., Jr, Minnick A. A., Jr, Dolence E. K., McKee J. A., Miller M. J., Lavoie M. C., Malouin F. Modes of action and inhibitory activities of new siderophore-beta-lactam conjugates that use specific iron uptake pathways for entry into bacteria. Antimicrob Agents Chemother. 1992 Oct;36(10):2166–2175. doi: 10.1128/aac.36.10.2166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carlone G. M., Thomas M. L., Rumschlag H. S., Sottnek F. O. Rapid microprocedure for isolating detergent-insoluble outer membrane proteins from Haemophilus species. J Clin Microbiol. 1986 Sep;24(3):330–332. doi: 10.1128/jcm.24.3.330-332.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Crosa J. H. Genetics and molecular biology of siderophore-mediated iron transport in bacteria. Microbiol Rev. 1989 Dec;53(4):517–530. doi: 10.1128/mr.53.4.517-530.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Deneer H. G., Potter A. A. Effect of iron restriction on the outer membrane proteins of Actinobacillus (Haemophilus) pleuropneumoniae. Infect Immun. 1989 Mar;57(3):798–804. doi: 10.1128/iai.57.3.798-804.1989. [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. Fenwick B. W., Osburn B. I., Olander H. J. Isolation and biological characterization of two lipopolysaccharides and a capsular-enriched polysaccharide preparation from Haemophilus pleuropneumoniae. Am J Vet Res. 1986 Jul;47(7):1433–1441. [PubMed] [Google Scholar]
  12. Foster L. A., Dyer D. W. A siderophore production mutant of Bordetella bronchiseptica cannot use lactoferrin as an iron source. Infect Immun. 1993 Jun;61(6):2698–2702. doi: 10.1128/iai.61.6.2698-2702.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gensberg K., Doyle E. J., Perry D. J., Smith A. W. Uptake of BRL 41897A, a C(7) alpha-formamido substituted cephalosporin, via the ferri-pyochelin transport system of Pseudomonas aeruginosa. J Antimicrob Chemother. 1994 Nov;34(5):697–705. doi: 10.1093/jac/34.5.697. [DOI] [PubMed] [Google Scholar]
  14. Gentry M. J., Confer A. W., Weinberg E. D., Homer J. T. Cytotoxin (leukotoxin) production by Pasteurella haemolytica: requirement for an iron-containing compound. Am J Vet Res. 1986 Sep;47(9):1919–1923. [PubMed] [Google Scholar]
  15. Gerlach G. F., Anderson C., Potter A. A., Klashinsky S., Willson P. J. Cloning and expression of a transferrin-binding protein from Actinobacillus pleuropneumoniae. Infect Immun. 1992 Mar;60(3):892–898. doi: 10.1128/iai.60.3.892-898.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ghosh M., Miller M. J. Design, synthesis, and biological evaluation of isocyanurate-based antifungal and macrolide antibiotic conjugates: iron transport-mediated drug delivery. Bioorg Med Chem. 1995 Nov;3(11):1519–1525. doi: 10.1016/0968-0896(95)00134-3. [DOI] [PubMed] [Google Scholar]
  17. Gonzalez G. C., Caamano D. L., Schryvers A. B. Identification and characterization of a porcine-specific transferrin receptor in Actinobacillus pleuropneumoniae. Mol Microbiol. 1990 Jul;4(7):1173–1179. doi: 10.1111/j.1365-2958.1990.tb00692.x. [DOI] [PubMed] [Google Scholar]
  18. Hu S. P., Felice L. J., Sivanandan V., Maheswaran S. K. Siderophore production by Pasteurella multocida. Infect Immun. 1986 Dec;54(3):804–810. doi: 10.1128/iai.54.3.804-810.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jacques M., Bélanger M., Diarra M. S., Dargis M., Malouin F. Modulation of Pasteurella multocida capsular polysaccharide during growth under iron-restricted conditions and in vivo. Microbiology. 1994 Feb;140(Pt 2):263–270. doi: 10.1099/13500872-140-2-263. [DOI] [PubMed] [Google Scholar]
  20. Klebba P. E., Rutz J. M., Liu J., Murphy C. K. Mechanisms of TonB-catalyzed iron transport through the enteric bacterial cell envelope. J Bioenerg Biomembr. 1993 Dec;25(6):603–611. doi: 10.1007/BF00770247. [DOI] [PubMed] [Google Scholar]
  21. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  22. Litwin C. M., Calderwood S. B. Role of iron in regulation of virulence genes. Clin Microbiol Rev. 1993 Apr;6(2):137–149. doi: 10.1128/cmr.6.2.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Martin P. G., Lachance P., Niven D. F. Production of RNA-dependent haemolysin by Haemophilus pleuropneumoniae. Can J Microbiol. 1985 May;31(5):456–462. doi: 10.1139/m85-085. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Menozzi F. D., Gantiez C., Locht C. Identification and purification of transferrin- and lactoferrin-binding proteins of Bordetella pertussis and Bordetella bronchiseptica. Infect Immun. 1991 Nov;59(11):3982–3988. doi: 10.1128/iai.59.11.3982-3988.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Miller M. J., McKee J. A., Minnick A. A., Dolence E. K. The design, synthesis and study of siderophore-antibiotic conjugates. Siderophore mediated drug transport. Biol Met. 1991;4(1):62–69. doi: 10.1007/BF01135559. [DOI] [PubMed] [Google Scholar]
  27. Minnick A. A., McKee J. A., Dolence E. K., Miller M. J. Iron transport-mediated antibacterial activity of and development of resistance to hydroxamate and catechol siderophore-carbacephalosporin conjugates. Antimicrob Agents Chemother. 1992 Apr;36(4):840–850. doi: 10.1128/aac.36.4.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  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. Neilands J. B., Bindereif A., Montgomerie J. Z. Genetic basis of iron assimilation in pathogenic Escherichia coli. Curr Top Microbiol Immunol. 1985;118:179–195. doi: 10.1007/978-3-642-70586-1_10. [DOI] [PubMed] [Google Scholar]
  31. Neilands J. B. Microbial iron compounds. Annu Rev Biochem. 1981;50:715–731. doi: 10.1146/annurev.bi.50.070181.003435. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Ogunnariwo J. A., Schryvers A. B. Iron acquisition in Pasteurella haemolytica: expression and identification of a bovine-specific transferrin receptor. Infect Immun. 1990 Jul;58(7):2091–2097. doi: 10.1128/iai.58.7.2091-2097.1990. [DOI] [PMC free article] [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. 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]
  36. Parrot M., Caufield P. W., Lavoie M. C. Preliminary characterization of four bacteriocins from Streptococcus mutans. Can J Microbiol. 1990 Feb;36(2):123–130. doi: 10.1139/m90-022. [DOI] [PubMed] [Google Scholar]
  37. Payne S. M. Iron acquisition in microbial pathogenesis. Trends Microbiol. 1993 May;1(2):66–69. doi: 10.1016/0966-842x(93)90036-q. [DOI] [PubMed] [Google Scholar]
  38. Postle K. TonB protein and energy transduction between membranes. J Bioenerg Biomembr. 1993 Dec;25(6):591–601. doi: 10.1007/BF00770246. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Silver S., Walderhaug M. Gene regulation of plasmid- and chromosome-determined inorganic ion transport in bacteria. Microbiol Rev. 1992 Mar;56(1):195–228. doi: 10.1128/mr.56.1.195-228.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Smith P. W., Chamiec A. J., Chung G., Cobley K. N., Duncan K., Howes P. D., Whittington A. R., Wood M. R. Synthesis and biological activity of novel cephalosporins containing a (Z)-vinyl dimethylphosphonate group. J Antibiot (Tokyo) 1995 Jan;48(1):73–82. doi: 10.7164/antibiotics.48.73. [DOI] [PubMed] [Google Scholar]
  42. Trudel L., Arriaga-Alba M., Lavoie M. C. Survey of drug and phage resistance and colicin and hemolysin production among coliforms isolated in the Ivory Coast. Appl Environ Microbiol. 1984 Oct;48(4):905–907. doi: 10.1128/aem.48.4.905-907.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. 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]
  44. Wooldridge K. G., Williams P. H. Iron uptake mechanisms of pathogenic bacteria. FEMS Microbiol Rev. 1993 Nov;12(4):325–348. doi: 10.1111/j.1574-6976.1993.tb00026.x. [DOI] [PubMed] [Google Scholar]
  45. Woolfrey B. F., Moody J. A. Human infections associated with Bordetella bronchiseptica. Clin Microbiol Rev. 1991 Jul;4(3):243–255. doi: 10.1128/cmr.4.3.243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Yates W. D. A review of infectious bovine rhinotracheitis, shipping fever pneumonia and viral-bacterial synergism in respiratory disease of cattle. Can J Comp Med. 1982 Jul;46(3):225–263. [PMC free article] [PubMed] [Google Scholar]

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