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Antimicrobial Agents and Chemotherapy, August 1998, p. 1952-1958, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Site-Specific Mutations in the 23S rRNA Gene of Helicobacter pylori Confer Two Types of Resistance to Macrolide-Lincosamide-Streptogramin B Antibiotics

Ge Wang and Diane E. Taylor*

Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada

Received 12 November 1997/Returned for modification 1 January 1998/Accepted 28 May 1998

Clarithromycin resistance in Helicobacter pylori is mainly due to A-to-G mutations within the peptidyltransferase region of the 23S rRNA. In the present study, cross-resistance to macrolide, lincosamide, and streptogramin B (MLS) antibiotics (MLS phenotypes) has been investigated for several clinical isolates of H. pylori. Two major types of MLS resistance were identified and correlated with specific point mutations in the 23S rRNA gene. The A2142G mutation was linked with high-level cross-resistance to all MLS antibiotics (type I), and the A2143G mutation gave rise to an intermediate level of resistance to clarithromycin and clindamycin but no resistance to streptogramin B (type II). In addition, streptogramin A and streptogramin B were demonstrated to have a synergistic effect on both MLS-sensitive and MLS-resistant H. pylori strains. To further understand the mechanism of MLS resistance in H. pylori, we performed in vitro site-directed mutagenesis (substitution of G, C, or T for A at either position 2142 or 2143 of the 23S rRNA gene). The site-directed point mutations were introduced into a clarithromycin-susceptible strain, H. pylori UA802, by natural transformation followed by characterization of their effects on MLS resistance in an isogenic background. Strains with A-to-G and A-to-C mutations at the same position within the 23S rRNA gene had similar levels of clarithromycin resistance, and this level of resistance was higher than that for strains with the A-to-T mutation. Mutations at position 2142 conferred a higher level of clarithromycin resistance than mutations at position 2143. All mutations at position 2142 conferred cross-resistance to all MLS antibiotics, which corresponds to the type I MLS phenotype, whereas mutations at position 2143 were associated with a type II MLS phenotype with no resistance to streptogramin B. To explain that A-to-G transitions were predominantly observed in clarithromycin-resistant clinical isolates, we propose a possible mechanism by which A-to-G mutations are preferentially produced in H. pylori.

* Corresponding author. Mailing address: Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. Phone: (403) 492-4777. Fax: (403) 492-7521. E-mail: diane.taylor{at}ualberta.ca.

Antimicrobial Agents and Chemotherapy, August 1998, p. 1952-1958, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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