Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1982 Nov;22(5):824–831. doi: 10.1128/aac.22.5.824

7-Hydroxytropolone: an inhibitor of aminoglycoside-2"-O-adenylyltransferase.

N E Allen, W E Alborn Jr, J N Hobbs Jr, H A Kirst
PMCID: PMC185667  PMID: 6185088

Abstract

Aminoglycoside-2"-O-adenylyltransferase was inhibited by 7-hydroxytropolone. Inhibition was competitive with respect to the cosubstrate ATP and appeared to require the unique vicinal arrangement of oxygens found in 7-hydroxytropolone. Combinations of 7-hydroxytropolone plus the appropriate aminoglycoside substrates were active against resistant bacteria possessing the adenylyltransferase. No potentiation was observed against other aminoglycoside-resistant or -susceptible strains. The fact that the inhibition of an aminoglycoside-modifying enzyme overcomes the poor uptake of aminoglycosides in resistant strains points to the singular importance of the inactivating enzyme as a determinant of resistance.

Full text

PDF
824

Selected References

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

  1. Ahmad M. H., Rechenmacher A., Böck A. Interaction between aminoglycoside uptake and ribosomal resistance mutations. Antimicrob Agents Chemother. 1980 Nov;18(5):798–806. doi: 10.1128/aac.18.5.798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benveniste R., Davies J. Mechanisms of antibiotic resistance in bacteria. Annu Rev Biochem. 1973;42:471–506. doi: 10.1146/annurev.bi.42.070173.002351. [DOI] [PubMed] [Google Scholar]
  3. Benveniste R., Davies J. R-factor mediated gentamicin resistance: A new enzyme which modifies aminoglycoside antibiotics. FEBS Lett. 1971 May 20;14(5):293–296. doi: 10.1016/0014-5793(71)80282-x. [DOI] [PubMed] [Google Scholar]
  4. Biddlecome S., Haas M., Davies J., Miller G. H., Rane D. F., Daniels P. J. Enzymatic modification of aminoglycoside antibiotics: a new 3-N-acetylating enzyme from a Pseudomonas aeruginosa isolate. Antimicrob Agents Chemother. 1976 Jun;9(6):951–955. doi: 10.1128/aac.9.6.951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bryan L. E., Van Den Elzen H. M. Effects of membrane-energy mutations and cations on streptomycin and gentamicin accumulation by bacteria: a model for entry of streptomycin and gentamicin in susceptible and resistant bacteria. Antimicrob Agents Chemother. 1977 Aug;12(2):163–177. doi: 10.1128/aac.12.2.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bryan L. E., Van Den Elzen H. M. Gentamicin accumulation by sensitive strains of Escherichia coli and Pseudomonas aeruginosa. J Antibiot (Tokyo) 1975 Sep;28(9):696–703. doi: 10.7164/antibiotics.28.696. [DOI] [PubMed] [Google Scholar]
  7. Bryan L. E., Van den Elzen H. M. Streptomycin accumulation in susceptible and resistant strains of Escherichia coli and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1976 Jun;9(6):928–938. doi: 10.1128/aac.9.6.928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brzezinska M., Davies J. Two enzymes which phosphorylate neomycin and kanamycin in Escherichia coli strains carrying R factors. Antimicrob Agents Chemother. 1973 Feb;3(2):266–269. doi: 10.1128/aac.3.2.266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cornish-Bowden A. A simple graphical method for determining the inhibition constants of mixed, uncompetitive and non-competitive inhibitors. Biochem J. 1974 Jan;137(1):143–144. doi: 10.1042/bj1370143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Davies J., Courvalin P., Berg D. Thoughts on the origins of resistance plasmids. J Antimicrob Chemother. 1977 Nov;3 (Suppl 100):7–17. doi: 10.1093/jac/3.suppl_c.7. [DOI] [PubMed] [Google Scholar]
  11. Dickie P., Bryan L. E., Pickard M. A. Effect of enzymatic adenylylation on dihydrostreptomycin accumulation in Escherichia coli carrying an R-factor: model explaining aminoglycoside resistance by inactivating mechanisms. Antimicrob Agents Chemother. 1978 Oct;14(4):569–580. doi: 10.1128/aac.14.4.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Doi O., Kondo S., Tanaka N., Umezawa H. Purification and properties of kanamycin-phosphorylating enzyme from Pseudomonas aeruginosa. J Antibiot (Tokyo) 1969 Jun;22(6):273–282. doi: 10.7164/antibiotics.22.273. [DOI] [PubMed] [Google Scholar]
  13. Fu K. P., Neu H. C. Comparative inhibition beta-lactamases by novel beta-lactam compounds. Antimicrob Agents Chemother. 1979 Feb;15(2):171–176. doi: 10.1128/aac.15.2.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Goldman P. R., Northrop D. B. Preparation of stable gentamicin adenylyl transferase of high specific activity. Biochem Biophys Res Commun. 1975 Oct 27;66(4):1408–1413. doi: 10.1016/0006-291x(75)90516-1. [DOI] [PubMed] [Google Scholar]
  15. Haas M. J., Dowding J. E. Aminoglycoside-modifying enzymes. Methods Enzymol. 1975;43:611–628. doi: 10.1016/0076-6879(75)43124-x. [DOI] [PubMed] [Google Scholar]
  16. Haas M., Biddlecome S., Davies J., Luce C. E., Daniels P. J. Enzymatic modification of aminoglycoside antibiotics: a new 6'-N-acetylating enzyme from a Pseudomonas aeruginosa isolate. Antimicrob Agents Chemother. 1976 Jun;9(6):945–950. doi: 10.1128/aac.9.6.945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hancock R. E. Aminoglycoside uptake and mode of action-with special reference to streptomycin and gentamicin. II. Effects of aminoglycosides on cells. J Antimicrob Chemother. 1981 Dec;8(6):429–445. doi: 10.1093/jac/8.6.429. [DOI] [PubMed] [Google Scholar]
  18. Hurwitz C., Braun C. B., Rosano C. L. Role of ribosome recycling in uptake of dihydrostreptomycin by sensitive and resistant Escherichia coli. Biochim Biophys Acta. 1981 Jan 29;652(1):168–176. doi: 10.1016/0005-2787(81)90220-3. [DOI] [PubMed] [Google Scholar]
  19. Höltje J. V. Induction of streptomycin uptake in resistant strains of Escherichia coli. Antimicrob Agents Chemother. 1979 Feb;15(2):177–181. doi: 10.1128/aac.15.2.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Höltje J. V. Streptomycin uptake via an inducible polyamine transport system in Escherichia coli. Eur J Biochem. 1978 May 16;86(2):345–351. doi: 10.1111/j.1432-1033.1978.tb12316.x. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Le Goffic F., Martel A., Capmau M. L., Baca B., Goebel P., Chardon H., Soussy C. J., Duval J., Bouanchaud D. H. New plasmid-mediated nucleotidylation of aminoglycoside antibiotics in Staphlococcus aureus. Antimicrob Agents Chemother. 1976 Aug;10(2):258–264. doi: 10.1128/aac.10.2.258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Martel A., Moreau N., Capmau M. L., Soussy C. J., Duval J. 2"-O-phosphorylation of gentamicin components by a Staphylococcus aureus strain carrying a plasmid. Antimicrob Agents Chemother. 1977 Jul;12(1):26–30. doi: 10.1128/aac.12.1.26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Miller G. H., Arcieri G., Weinstein M. J., Waitz J. A. Biological activity of netilmicin, a broad-spectrum semisynthetic aminoglycoside antibiotic. Antimicrob Agents Chemother. 1976 Nov;10(5):827–836. doi: 10.1128/aac.10.5.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Neu H. C., Fu K. P. Clavulanic acid, a novel inhibitor of beta-lactamases. Antimicrob Agents Chemother. 1978 Nov;14(5):650–655. doi: 10.1128/aac.14.5.650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nugent M. E., Bone D. H., Datta N. A transposon, Tn732, encoding gentamicin/tobramycin resistance. Nature. 1979 Nov 22;282(5737):422–423. doi: 10.1038/282422a0. [DOI] [PubMed] [Google Scholar]
  27. Price K. E., Godfrey J. C. Effect of structural modifications on the biological properties of aminoglycoside antibiotics containing 2-deoxystreptamine. Adv Appl Microbiol. 1974;18(0):191–307. doi: 10.1016/s0065-2164(08)70572-0. [DOI] [PubMed] [Google Scholar]
  28. Smith A. L., Smith D. H. Gentamicin:adenine mononucleotide transferase: partial purification, characterization, and use in the clinical quantitation of gentamicin. J Infect Dis. 1974 Apr;129(4):391–401. doi: 10.1093/infdis/129.4.391. [DOI] [PubMed] [Google Scholar]
  29. Umezawa H. Biochemical mechanism of resistance to aminoglycosidic antibiotics. Adv Carbohydr Chem Biochem. 1974;30:183–225. doi: 10.1016/s0065-2318(08)60265-6. [DOI] [PubMed] [Google Scholar]
  30. Umezawa H., Yamamoto H., Yagisawa M., Kondo S., Takeuchi T. Letter: Kanamycin phosphotransferase. I. Mechanism of cross resistance between kanamycin and lividomycin. J Antibiot (Tokyo) 1973 Jul;26(7):407–411. doi: 10.7164/antibiotics.26.407. [DOI] [PubMed] [Google Scholar]
  31. Vastola A. P., Altschaefl J., Harford S. 5-epi-Sisomicin and 5-epi-Gentamicin B: substrates for aminoglycoside-modifying enzymes that retain activity against aminoglycoside-resistant bacteria. Antimicrob Agents Chemother. 1980 May;17(5):798–802. doi: 10.1128/aac.17.5.798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Williams J. W., Northrop D. B. Synthesis of a tight-binding, multisubstrate analog inhibitor of gentamicin acetyltransferase I. J Antibiot (Tokyo) 1979 Nov;32(11):1147–1154. doi: 10.7164/antibiotics.32.1147. [DOI] [PubMed] [Google Scholar]
  33. Yagisawa M., Davies J. E. Possible homology between genes for two aminoglycoside nucleotidyltransferases, AAD(3'') and ANT(2''): an evolutionary relationship? J Antibiot (Tokyo) 1979 Mar;32(3):250–253. doi: 10.7164/antibiotics.32.250. [DOI] [PubMed] [Google Scholar]

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

RESOURCES