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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.



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