Abstract
Tetracycline-resistant Helicobacter pylori strains have been increasingly reported worldwide. However, only a small number of tetracycline-resistant strains have been studied with regard to possible mechanisms of resistance and those studies have focused on mutations in the tetracycline binding sites of 16S rRNA-encoding genes. We here report studies of 41 tetracycline-resistant H. pylori strains (tetracycline MICs, 4 to 32 microg/ml) from North America (n = 12) and from East Asia (n = 29). DNA sequence analyses of 16S rRNA-encoding genes revealed that 22 (54%) of the resistant isolates carried one of five different single-nucleotide substitutions (CGA, GGA, TGA, AGC, or AGT) at the putative tetracycline binding site (AGA(965-967)). Single-nucleotide substitutions were associated with reduced ribosomal binding and with slightly increased tetracycline MICs (1 to 2 microg/ml). The 19 tetracycline-resistant isolates with no detectable mutations in the tetracycline binding site had normal tetracycline-ribosome binding. All tetracycline-resistant isolates, including those with and those without mutations in the tetracycline binding site, showed decreased accumulation of tetracycline. These results suggest that tetracycline resistance is multifactorial, involving alterations both in ribosomal binding and in membrane permeability.
Highlights
Helicobacter pylori infection is etiologically associated with chronic gastritis, peptic ulcers, gastric adenocarcinoma, and primary gastric lymphoma [4, 10]
Tetracycline is a major component of quadruple therapy for H. pylori infection, and resistant H. pylori strains are presently uncommon in the United States and Europe [1, 21]
The transformants ATCC 700392/KH84B and ATCC 700392/KH179A, did not have detectable mutations at any of the putative tetracycline binding sites. These results suggest that a singlenucleotide substitution in the 16S rRNA-encoding genes is associated with low levels of tetracycline resistance, additional determinants transferred from the donor genomic DNA to the susceptible H. pylori strains are needed to produce tetracycline MICs in the range of 4 to 8 g/ml
Summary
Helicobacter pylori infection is etiologically associated with chronic gastritis, peptic ulcers, gastric adenocarcinoma, and primary gastric lymphoma [4, 10]. Tetracycline is a major component of quadruple therapy for H. pylori infection, and resistant H. pylori strains are presently uncommon in the United States and Europe [1, 21]. Uted to mutations in the 16S rRNA-encoding genes that affect the binding site of tetracycline [8, 35]. Studies of an isolate from The Netherlands [8] and of two isolates from Australia [35] showed that high-level tetracycline resistance (MIC, 8 to 64 g/ml) was associated with triple mutations (AGA965–967 to TTC) at the putative tetracycline binding site of the 16S rRNA-encoding genes. We report characterization of tetracycline-resistant clinical H. pylori isolates from North America (United States and Canada) and East Asia (Korea and Japan), only approximately half of which had alterations in the putative tetracycline binding sites of 16S rRNA-encoding genes
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