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Antimicrobial Agents and Chemotherapy, November 2006, p. 3816-3823, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00767-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

23S rRNA 2058A->G Alteration Mediates Ketolide Resistance in Combination with Deletion in L22{triangledown}

Rita Berisio,1 Natascia Corti,2 Peter Pfister,2 Ada Yonath,3* and Erik C. Böttger2

Institute of Biostructure and Bioimaging, CNR, Naples, Italy,1 Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastr. 30/32, CH-8006 Zürich, Switzerland,2 Department for Structural Biology, Weizmann Institute of Science, Rehovot, Israel3

Received 23 June 2006/ Returned for modification 8 August 2006/ Accepted 15 August 2006

Resistance to macrolides and ketolides occurs mainly via alterations in RNA moieties of the drug-binding site. Using an A2058G mutant of Mycobacterium smegmatis, additional telithromycin resistance was acquired via deletion of 15 residues from protein L22. Molecular modeling, based on the crystal structure of the large ribosomal subunit from Deinococcus radiodurans complexed with telithromycin, shows that the telithromycin carbamate group is located in the proximity of the tip of the L22 hairpin-loop, allowing for weak interactions between them. These weak interactions may become more important once the loss of A2058 interactions destabilizes drug binding, presumably resulting in a shift of the drug toward the other side of the tunnel, namely, to the vicinity of L22. Hence, the deletion of 15 residues from L22 may further destabilize telithromycin binding and confer telithromycin resistance. Such deletions may also lead to notable differences in the tunnel outline, as well as to an increase of its diameter to a size, allowing the progression of the nascent chain.

* Corresponding author. Mailing address: Department for Structural Biology, Weizmann Institute of Science, Rehovot, Israel. Phone: 972-8-934-3028. Fax: 972-8-934-4154. E-mail: ada.yonath{at}weizmann.ac.il.

{triangledown} Published ahead of print on 21 August 2006.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3816-3823, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00767-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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