This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Long, K. S.
Right arrow Articles by Vester, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Long, K. S.
Right arrow Articles by Vester, B.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, April 2006, p. 1458-1462, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1458-1462.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Interaction of Pleuromutilin Derivatives with the Ribosomal Peptidyl Transferase Center

Katherine S. Long,1* Lykke H. Hansen,2 Lene Jakobsen,2 and Birte Vester2

Institute of Molecular Biology and Physiology, University of Copenhagen, Sølvgade 83 H, DK-1307 Copenhagen K, Denmark,1 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark2

Received 13 September 2005/ Returned for modification 2 November 2005/ Accepted 13 January 2006

Tiamulin is a pleuromutilin antibiotic that is used in veterinary medicine. The recently published crystal structure of a tiamulin-50S ribosomal subunit complex provides detailed information about how this drug targets the peptidyl transferase center of the ribosome. To promote rational design of pleuromutilin-based drugs, the binding of the antibiotic pleuromutilin and three semisynthetic derivatives with different side chain extensions has been investigated using chemical footprinting. The nucleotides A2058, A2059, G2505, and U2506 are affected in all of the footprints, suggesting that the drugs are similarly anchored in the binding pocket by the common tricyclic mutilin core. However, varying effects are observed at U2584 and U2585, indicating that the side chain extensions adopt distinct conformations within the cavity and thereby affect the rRNA conformation differently. An Escherichia coli L3 mutant strain is resistant to tiamulin and pleuromutilin, but not valnemulin, implying that valnemulin is better able to withstand an altered rRNA binding surface around the mutilin core. This is likely due to additional interactions made between the valnemulin side chain extension and the rRNA binding site. The data suggest that pleuromutilin drugs with enhanced antimicrobial activity may be obtained by maximizing the number of interactions between the side chain moiety and the peptidyl transferase cavity.

* Corresponding author. Mailing address: Institute of Molecular Biology and Physiology, University of Copenhagen, Sølvgade 83 H, DK-1307 Copenhagen K, Denmark. Phone: (45) 35 32 20 30. Fax: (45) 35 32 20 40. E-mail: long{at}mermaid.molbio.ku.dk.

Antimicrobial Agents and Chemotherapy, April 2006, p. 1458-1462, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1458-1462.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Woodford, N., Afzal-Shah, M., Warner, M., Livermore, D. M. (2008). In vitro activity of retapamulin against Staphylococcus aureus isolates resistant to fusidic acid and mupirocin. J Antimicrob Chemother 62: 766-768 [Abstract] [Full Text]  
  • Miller, K., Dunsmore, C. J., Fishwick, C. W. G., Chopra, I. (2008). Linezolid and Tiamulin Cross-Resistance in Staphylococcus aureus Mediated by Point Mutations in the Peptidyl Transferase Center. Antimicrob. Agents Chemother. 52: 1737-1742 [Abstract] [Full Text]  
  • Champney, W. S., Rodgers, W. K. (2007). Retapamulin Inhibition of Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureus Cells. Antimicrob. Agents Chemother. 51: 3385-3387 [Abstract] [Full Text]  
  • Davidovich, C., Bashan, A., Auerbach-Nevo, T., Yaggie, R. D., Gontarek, R. R., Yonath, A. (2007). Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity. Proc. Natl. Acad. Sci. USA 104: 4291-4296 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»