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Antimicrobial Agents and Chemotherapy, April 2009, p. 1411-1419, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01425-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Distinct Mode of Interaction of a Novel Ketolide Antibiotic That Displays Enhanced Antimicrobial Activity {triangledown}

Ekaterini C. Kouvela,1 Dimitrios L. Kalpaxis,1 Daniel N. Wilson,2 and George P. Dinos1*

Laboratory of Biochemistry, School of Medicine, University of Patras, 26500 Patras, Greece,1 Center for Integrated Protein Science Munich CiPSM, and Gene Center and Department of Chemistry and Biochemistry, Ludwig-Maximilians-Universität Munchen, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany2

Received 23 October 2008/ Returned for modification 1 December 2008/ Accepted 2 January 2009

Ketolides represent the latest generation of macrolide antibiotics, displaying improved activities against some erythromycin-resistant strains, while maintaining their activity against erythromycin-susceptible ones. In this study, we present a new ketolide, K-1325, that carries an alkyl-aryl side chain at C-13 of the lactone ring. According to our genetic and biochemical studies, K-1325 binds within the nascent polypeptide exit tunnel, at a site previously described as the primary attachment site of all macrolide antibiotics. Compared with telithromycin, K-1325 displays enhanced antimicrobial activity against wild-type Escherichia coli strains, as well as against strains bearing the U2609C mutation in 23S rRNA. Chemical protection experiments showed that the alkyl-aryl side chain of K-1325 interacts specifically with helix 35 of 23S rRNA, a fact leading to an increased affinity of U2609C mutant ribosomes for the drug and rationalizing the enhanced effectiveness of this new ketolide.

* Corresponding author. Mailing address: Laboratory of Biochemistry, School of Medicine, University of Patras, 26500 Patras, Greece. Phone: 302610-996259. Fax: 302610-969167. E-mail: dinosg{at}upatras.gr

{triangledown} Published ahead of print on 21 January 2009.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1411-1419, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01425-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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