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Antimicrobial Agents and Chemotherapy, September 2001, p. 2414-2419, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2414-2419.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Aminoglycoside Resistance with Homogeneous and Heterogeneous Populations of Antibiotic-Resistant Ribosomes

Michael I. Rechtdagger and Joseph D. Puglisi*

Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305-5126

Received 8 February 2001/Returned for modification 30 March 2001/Accepted 24 May 2001

Aminoglycosides bind to rRNA in the small subunit of the bacterial ribosome. Mutations in the decoding region of 16S rRNA confer resistance to specific subsets of aminoglycoside antibiotics. The two major classes of 2-deoxystreptamine aminoglycosides are the 4,5- and the 4,6-disubstituted antibiotics. Antibiotics of the 4,5-disubstituted class include neomycin, paromomycin, and ribostamycin. Gentamicins and kanamycins belong to the 4,6-disubstituted class of aminoglycosides. Structural studies indicated the potential importance of position 1406 (Escherichia coli numbering) in the binding of ring III of the 4,6-disubstituted class of aminoglycosides to 16S rRNA. We have introduced a U1406-to-A mutation in a plasmid-encoded copy of E. coli 16S rRNA which has been expressed either in a mixture with wild-type ribosomes or in a strain in which all rRNA is transcribed from the plasmid-encoded rrn operon. High-level resistance to many of the 4,6-disubstituted aminoglycosides is observed only when all the rRNA contains the U1406-to-A mutation. In contrast to the partial dominance of resistance observed with other mutations in the decoding region, there is a dominance of sensitivity with the 1406A mutation. Chemical footprinting experiments indicate that resistance arises from a reduced affinity of the antibiotic for the rRNA target. These results demonstrate that although position 1406 is an important determinant in the binding and action of the 4,6-disubstituted aminoglycosides, other rRNA mutations that perturb the binding of ring I of both classes of 2-deoxystreptamine aminoglycosides confer higher levels of resistance as well as a partial dominance of resistance.

* Corresponding author. Mailing address: Department of Structural Biology, Stanford University School of Medicine, D105 Fairchild Bldg., Stanford, CA 94305-5126. Phone: (650) 498-4397. Fax: (650) 723-8464. E-mail: puglisi{at}stanford.edu.

dagger Present address: Department of Molecular Biology, MB33, The Scripps Research Institute, La Jolla, CA 92037.

Antimicrobial Agents and Chemotherapy, September 2001, p. 2414-2419, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2414-2419.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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