Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1996 Jul;40(7):1640–1644. doi: 10.1128/aac.40.7.1640

Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli.

P E Brandish 1, K I Kimura 1, M Inukai 1, R Southgate 1, J T Lonsdale 1, T D Bugg 1
PMCID: PMC163387  PMID: 8807054

Abstract

Using a continuous fluorescence-based enzyme assay, we have characterized the antibacterial agents tumicamycin and liposidomycin B as inhibitors of solubilized Escherichia coli phospho-N-acetylmuramyl-pentapeptide translocase. Tunicamycin exhibited reversible inhibition (Ki = 0.55 +/- 0.1 microM) which was noncompetitive with respect to the lipid acceptor substrate and competitive with respect to the fluorescent substrate analog, dansyl-UDPMurNAc-pentapeptide. Liposidomycin B exhibited slow-binding inhibition (Ki = 80 +/- 15 nM) which was competitive with respect to the lipid acceptor substrate and noncompetitive with respect to dansyl-UDPMurNAc-pentapeptide. These results provide insight into the molecular mechanisms of action of these two classes of nucleoside antibiotics.

Full Text

The Full Text of this article is available as a PDF (267.4 KB).

Selected References

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

  1. Banerjee D. K. Amphomycin inhibits mannosylphosphoryldolichol synthesis by forming a complex with dolichylmonophosphate. J Biol Chem. 1989 Feb 5;264(4):2024–2028. [PubMed] [Google Scholar]
  2. Brandish P. E., Burnham M. K., Lonsdale J. T., Southgate R., Inukai M., Bugg T. D. Slow binding inhibition of phospho-N-acetylmuramyl-pentapeptide-translocase (Escherichia coli) by mureidomycin A. J Biol Chem. 1996 Mar 29;271(13):7609–7614. doi: 10.1074/jbc.271.13.7609. [DOI] [PubMed] [Google Scholar]
  3. Bugg T. D., Walsh C. T. Intracellular steps of bacterial cell wall peptidoglycan biosynthesis: enzymology, antibiotics, and antibiotic resistance. Nat Prod Rep. 1992 Jun;9(3):199–215. doi: 10.1039/np9920900199. [DOI] [PubMed] [Google Scholar]
  4. Heifetz A., Keenan R. W., Elbein A. D. Mechanism of action of tunicamycin on the UDP-GlcNAc:dolichyl-phosphate Glc-NAc-1-phosphate transferase. Biochemistry. 1979 May 29;18(11):2186–2192. doi: 10.1021/bi00578a008. [DOI] [PubMed] [Google Scholar]
  5. Heydanek M. G., Jr, Struve W. G., Neuhaus F. C. On the initial stage in peptidoglycan synthesis. 3. Kinetics and uncoupling of phospho-N-acetylmuramyl-pentapeptide translocase (uridine 5'-phosphate). Biochemistry. 1969 Mar;8(3):1214–1221. doi: 10.1021/bi00831a056. [DOI] [PubMed] [Google Scholar]
  6. Higashi Y., Strominger J. L., Sweeley C. C. Structure of a lipid intermediate in cell wall peptidoglycan synthesis: a derivative of a C55 isoprenoid alcohol. Proc Natl Acad Sci U S A. 1967 Jun;57(6):1878–1884. doi: 10.1073/pnas.57.6.1878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Inukai M., Isono F., Takahashi S., Enokita R., Sakaida Y., Haneishi T. Mureidomycins A-D, novel peptidylnucleoside antibiotics with spheroplast forming activity. I. Taxonomy, fermentation, isolation and physico-chemical properties. J Antibiot (Tokyo) 1989 May;42(5):662–666. doi: 10.7164/antibiotics.42.662. [DOI] [PubMed] [Google Scholar]
  8. Inukai M., Isono F., Takatsuki A. Selective inhibition of the bacterial translocase reaction in peptidoglycan synthesis by mureidomycins. Antimicrob Agents Chemother. 1993 May;37(5):980–983. doi: 10.1128/aac.37.5.980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Isono F., Inukai M. Mureidomycin A, a new inhibitor of bacterial peptidoglycan synthesis. Antimicrob Agents Chemother. 1991 Feb;35(2):234–236. doi: 10.1128/aac.35.2.234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Isono F., Katayama T., Inukai M., Haneishi T. Mureidomycins A-D, novel peptidylnucleoside antibiotics with spheroplast forming activity. III. Biological properties. J Antibiot (Tokyo) 1989 May;42(5):674–679. doi: 10.7164/antibiotics.42.674. [DOI] [PubMed] [Google Scholar]
  11. Isono K., Uramoto M., Kusakabe H., Kimura K., Isaki K., Nelson C. C., McCloskey J. A. Liposidomycins: novel nucleoside antibiotics which inhibit bacterial peptidoglycan synthesis. J Antibiot (Tokyo) 1985 Nov;38(11):1617–1621. doi: 10.7164/antibiotics.38.1617. [DOI] [PubMed] [Google Scholar]
  12. Neu H. C. The crisis in antibiotic resistance. Science. 1992 Aug 21;257(5073):1064–1073. doi: 10.1126/science.257.5073.1064. [DOI] [PubMed] [Google Scholar]
  13. Smith P. K., Krohn R. I., Hermanson G. T., Mallia A. K., Gartner F. H., Provenzano M. D., Fujimoto E. K., Goeke N. M., Olson B. J., Klenk D. C. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985 Oct;150(1):76–85. doi: 10.1016/0003-2697(85)90442-7. [DOI] [PubMed] [Google Scholar]
  14. Struve W. G., Sinha R. K., Neuhaus F. C. On the initial stage in peptidoglycan synthesis. Phospho-N-acetylmuramyl-pentapeptide translocase (uridine monophosphate). Biochemistry. 1966 Jan;5(1):82–93. doi: 10.1021/bi00865a012. [DOI] [PubMed] [Google Scholar]
  15. Swartz M. N. Hospital-acquired infections: diseases with increasingly limited therapies. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2420–2427. doi: 10.1073/pnas.91.7.2420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Tanaka H., Oiwa R., Matsukura S., Omura S. Amphomycin inhibits phospho-N-acetylmuramyl-pentapeptide translocase in peptidoglycan synthesis of Bacillus. Biochem Biophys Res Commun. 1979 Feb 14;86(3):902–908. doi: 10.1016/0006-291x(79)91797-2. [DOI] [PubMed] [Google Scholar]

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

RESOURCES