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Antimicrobial Agents and Chemotherapy, September 2003, p. 2892-2896, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2892-2896.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Resistance to the Peptidyl Transferase Inhibitor Tiamulin Caused by Mutation of Ribosomal Protein L3

Jacob Bøsling,1 Susan M. Poulsen,1 Birte Vester,2 and Katherine S. Long1*

Institute of Molecular Biology, University of Copenhagen, DK-1307 Copenhagen K,1 Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark2

Received 7 April 2003/ Returned for modification 23 May 2003/ Accepted 11 June 2003

The antibiotic tiamulin targets the 50S subunit of the bacterial ribosome and interacts at the peptidyl transferase center. Tiamulin-resistant Escherichia coli mutants were isolated in order to elucidate mechanisms of resistance to the drug. No mutations in the rRNA were selected as resistance determinants using a strain expressing only a plasmid-encoded rRNA operon. Selection in a strain with all seven chromosomal rRNA operons yielded a mutant with an A445G mutation in the gene coding for ribosomal protein L3, resulting in an Asn149Asp alteration. Complementation experiments and sequencing of transductants demonstrate that the mutation is responsible for the resistance phenotype. Chemical footprinting experiments show a reduced binding of tiamulin to mutant ribosomes. It is inferred that the L3 mutation, which points into the peptidyl transferase cleft, causes tiamulin resistance by alteration of the drug-binding site. This is the first report of a mechanism of resistance to tiamulin unveiled in molecular detail.

* Corresponding author. Mailing address: Institute of Molecular Biology, University of Copenhagen, Sølvgade 83H, DK-1307, Copenhagen K, Denmark. Phone: (45) 35 32 20 23. Fax: (45) 35 32 20 40. E-mail: long{at}mermaid.molbio.ku.dk.

Antimicrobial Agents and Chemotherapy, September 2003, p. 2892-2896, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2892-2896.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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