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Antimicrobial Agents and Chemotherapy, August 2002, p. 2349-2357, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2349-2357.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Analysis of Penicillin-Binding Protein Genes of Clinical Isolates of Streptococcus pneumoniae with Reduced Susceptibility to Amoxicillin

Mignon du Plessis,1* Edouard Bingen,2 and Keith P. Klugman1,3

Pneumococcal Diseases Research Unit of the Medical Research Council, National Health Laboratory Service and University of the Witwatersrand, Johannesburg 2000, South Africa,1 Laboratoire de Microbiologie, Hôpital Robert Debré, 75019 Paris, France,2 Department of International Health, The Rollins School of Public Health, Emory University, Atlanta, Georgia 303223

Received 6 July 2001/ Returned for modification 12 November 2001/ Accepted 19 April 2002

The recent emergence of pneumococcal isolates exhibiting an unusual resistance phenotype of higher amoxicillin MICs in relation to the penicillin MICs prompted an analysis of the pbp genes from three such strains isolated in France. For comparison, three amoxicillin-susceptible strains were included in the study. DNA sequence analysis of the pbp2x, pbp2b, and pbp1a genes revealed extensive sequence divergence in all six isolates compared to the sequences of the genes of penicillin-susceptible strain R6. With the exception of pbp2b, no amino acid mutations were unique to the resistant isolates. Transformation experiments with cloned pbp genes isolated from one of the resistant isolates demonstrated a stepwise development of amoxicillin resistance involving penicillin-binding proteins (PBPs) 2X, 2B, and 1A. Full resistance, equivalent to that of the donor strain, was achieved only when genomic DNA was transformed into R62x/2b/1a mutants, suggesting that full resistance development in this isolate is mediated by a non-PBP determinant. Moreover, the recently identified murMN resistance determinant does not appear to have any impact on resistance in this isolate. This determinant (from the French isolate) was, however, able to transform an R6 mutant harboring pbp2x, pbp2b, and pbp1a genes from a Hungarian clone with an extremely high level of penicillin resistance so that it had increased levels of penicillin resistance. These results indicate that the development of high-level ß-lactam resistance is a complex process and that the involvement of MurMN in penicillin resistance appears to be dependent on specific mutations in PBPs 2X, 2B, and/or 1A. Furthermore, an additional (as yet unidentified) non-PBP-mediated resistance determinant is required for full resistance development in some pneumococci.

* Corresponding author. Mailing address: Pneumococcal Diseases Research Unit of the Medical Research Council, National Health Laboratory Service and University of the Witwatersrand, de Korte St., Hillbrow, P.O. Box 1038, Johannesburg 2000, South Africa. Phone: 27 11 489 9335. Fax: 27 11 489 9332. E-mail: mignondp{at}hotmail.com.

Antimicrobial Agents and Chemotherapy, August 2002, p. 2349-2357, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2349-2357.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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