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Antimicrobial Agents and Chemotherapy, December 2002, p. 3940-3946, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3940-3946.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Emergence of Tetracycline Resistance in Helicobacter pylori: Multiple Mutational Changes in 16S Ribosomal DNA and Other Genetic Loci

Daiva Dailidiene,1 M. Teresita Bertoli,1,2 Jolanta Miciuleviciene,1,3 Asish K. Mukhopadhyay,1 Giedrius Dailide,1 Mario Alberto Pascasio,4 Limas Kupcinskas,3 and Douglas E. Berg1*

Departments of Molecular Microbiology and Genetics, Washington University Medical School, St. Louis, Missouri 63110,1 Departamento de Ciencias Fisiológicas, Escuela de Medicina, Universidad Dr. José Matias Delgado, La Libertad,2 Servicio de Gastroenterología, Hospital Rosales, San Salvador, El Salvador,4 Department of Gastroenterology, Kaunas University of Medicine, Kaunas, 3000, Lithuania3

Received 20 May 2002/ Returned for modification 20 July 2002/ Accepted 25 August 2002

Tetracycline is useful in combination therapies against the gastric pathogen Helicobacter pylori. We found 6 tetracycline-resistant (Tetr) strains among 159 clinical isolates (from El Salvador, Lithuania, and India) and obtained the following four results: (i) 5 of 6 Tetr isolates contained one or two nucleotide substitutions in one part of the primary tetracycline binding site in 16S rRNA (AGA965-967 [Escherichia coli coordinates] changed to gGA, AGc, guA, or gGc [lowercase letters are used to represent the base changes]), whereas the sixth (isolate Ind75) retained AGA965-967; (ii) PCR products containing mutant 16S ribosomal DNA (rDNA) alleles transformed recipient strains to Tetr phenotypes, but transformants containing alleles with single substitutions (gGA and AGc) were less resistant than their Tetr parents; (iii) each of 10 Tetr mutants of reference strain 26695 (in which mutations were induced with metronidazole, a mutagenic anti-H. pylori agent) contained the normal AGA965-967 sequence; and (iv) transformant derivatives of Ind75 and of one of the Tetr 26695 mutants that had acquired mutant rDNA alleles were resistant to tetracycline at levels higher than those to which either parent strain was resistant. Thus, tetracycline resistance in H. pylori results from an accumulation of changes that may affect tetracycline-ribosome affinity and/or other functions (perhaps porins or efflux pumps). We suggest that the rarity of tetracycline resistance among clinical isolates reflects this need for multiple mutations and perhaps also the deleterious effects of such mutations on fitness. Formally equivalent mutations with small but additive effects are postulated to contribute importantly to traits such as host specificity and virulence and to H. pylori's great genetic diversity.

* Corresponding author. Mailing address: Department of Molecular Microbiology, Campus Box 8230, Washington University Medical School, 4940 Parkview Place, St. Louis, MO 63110. Phone: (314) 362-2772. Fax: (314) 362-1232 or (314) 362-7325. E-mail: BERG{at}BORCIM.WUSTL.EDU.

Antimicrobial Agents and Chemotherapy, December 2002, p. 3940-3946, Vol. 46, No. 12
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.12.3940-3946.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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