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Antimicrobial Agents and Chemotherapy, July 2002, p. 2229-2233, Vol. 46, No. 7
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.7.2229-2233.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Alterations in Penicillin-Binding Protein 1A Confer Resistance to ß-Lactam Antibiotics in Helicobacter pylori

M. M. Gerrits,1,2 D. Schuijffel,2 A. A. van Zwet,3 E. J. Kuipers,1 C. M. J. E. Vandenbroucke-Grauls,2 and J. G. Kusters1,2*

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam,1 Department of Medical Microbiology, Faculty of Medicine, Vrije Universiteit, Amsterdam,2 Medical Microbiology, Regional Public Health Laboratory Groningen/Drenthe, Hoogeveen, The Netherlands3

Received 21 September 2001/ Returned for modification 29 November 2001/ Accepted 12 April 2002

Most Helicobacter pylori strains are susceptible to amoxicillin, an important component of combination therapies for H. pylori eradication. The isolation and initial characterization of the first reported stable amoxicillin-resistant clinical H. pylori isolate (the Hardenberg strain) have been published previously, but the underlying resistance mechanism was not described. Here we present evidence that the ß-lactam resistance of the Hardenberg strain results from a single amino acid substitution in HP0597, a penicillin-binding protein 1A (PBP1A) homolog of Escherichia coli. Replacement of the wild-type HP0597 (pbp1A) gene of the amoxicillin-sensitive (Amxs) H. pylori strain 1061 by the Hardenberg pbp1A gene resulted in a 100-fold increase in the MIC of amoxicillin. Sequence analysis of pbp1A of the Hardenberg strain, the Amxs H. pylori strain 1061, and four amoxicillin-resistant (Amxr) 1061 transformants revealed a few amino acid substitutions, of which only a single Ser414->Arg substitution was involved in amoxicillin resistance. Although we cannot exclude that mutations in other genes are required for high-level amoxicillin resistance of the Hardenberg strain, this amino acid substitution in PBP1A resulted in an increased MIC of amoxicillin that was almost identical to that for the original Hardenberg strain.

* Corresponding author. Mailing address: Department of Gastroenterology and Hepatology, Rm. L448, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. Phone: 31-10-4635946. Fax: 31-10-4634682. E-mail: Kusters{at}mdl.azr.nl.

Antimicrobial Agents and Chemotherapy, July 2002, p. 2229-2233, Vol. 46, No. 7
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.7.2229-2233.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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