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Antimicrobial Agents and Chemotherapy, November 2006, p. 3875-3881, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00184-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Biochemical Characterization of the Interactions of the Novel Pleuromutilin Derivative Retapamulin with Bacterial Ribosomes{triangledown}

Kang Yan,* Lenore Madden, Anthony E. Choudhry, Christine S. Voigt,{dagger} Robert A. Copeland, and Richard R. Gontarek

Department of Enzymology and Mechanistic Pharmacology, GlaxoSmithKline Pharmaceuticals, 1250 S. Collegeville Rd., UP1345, Collegeville, Pennsylvania 19426

Received 10 February 2006/ Returned for modification 19 April 2006/ Accepted 21 August 2006

Retapamulin is a semisynthetic pleuromutilin derivative being developed as a topical antibiotic for treating bacterial infections of the skin. It is potent in vitro against susceptible and multidrug-resistant organisms commonly associated with bacterial skin infections. We report detailed mode of action studies demonstrating that retapamulin binds to the bacterial ribosome with high affinity, inhibits ribosomal peptidyl transferase activity, and partially inhibits the binding of the initiator tRNA substrate to the ribosomal P-site. Taken together, these data distinguish the mode of action of retapamulin from that of other classes of antibiotics. This unique mode of action may explain the lack of clinically relevant, target-specific cross-resistance of retapamulin with antibacterials in current use.

* Corresponding author. Mailing address: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426. Phone: (610) 917-7282. Fax: (610) 917-7901. E-mail: kang.2.yan{at}gsk.com.

{triangledown} Published ahead of print on 28 August 2006.

{dagger} Present address: sanofi-aventis, 11 Great Valley Parkway, Malvern, PA 19355.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3875-3881, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00184-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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