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

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Abstract
Tetracycline is useful in combination therapies against the gastric pathogen Helicobacter pylori . We found 6 tetracycline-resistant (Tet r ) strains among 159 clinical isolates (from El Salvador, Lithuania, and India) and obtained the following four results: (i) 5 of 6 Tet r isolates contained one or two nucleotide substitutions in one part of the primary tetracycline binding site in 16S rRNA (AGA 965-967 [ 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 AGA 965-967 ; (ii) PCR products containing mutant 16S ribosomal DNA (rDNA) alleles transformed recipient strains to Tet r phenotypes, but transformants containing alleles with single substitutions (gGA and AGc) were less resistant than their Tet r parents; (iii) each of 10 Tet r mutants of reference strain 26695 (in which mutations were induced with metronidazole, a mutagenic anti- H. pylori agent) contained the normal AGA 965-967 sequence; and (iv) transformant derivatives of Ind75 and of one of the Tet r 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.

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