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Antimicrobial Agents and Chemotherapy, May 2002, p. 1273-1280, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1273-1280.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Effects of Amino Acid Alterations in Penicillin-Binding Proteins (PBPs) 1a, 2b, and 2x on PBP Affinities of Penicillin, Ampicillin, Amoxicillin, Cefditoren, Cefuroxime, Cefprozil, and Cefaclor in 18 Clinical Isolates of Penicillin-Susceptible, -Intermediate, and -Resistant Pneumococci

Kensuke Nagai,1 Todd A. Davies,1 Michael R. Jacobs,2 and Peter C. Appelbaum1*

Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania,1 Department of Pathology, Case Western Reserve University, Cleveland, Ohio2

Received 15 October 2001/ Returned for modification 7 January 2002/ Accepted 24 January 2002

Amino acid alterations in or flanking conserved motifs making up the active binding sites of penicillin-binding proteins (PBPs) 1a, 2b, and 2x of pneumococci were correlated with changes in affinities of penicillin, ampicillin, amoxicillin, cefditoren, cefuroxime, cefprozil, and cefaclor for these PBPs. Four penicillin-susceptible (PSSP), eight penicillin-intermediate (PISP), and six penicillin-resistant (PRSP) pneumococci were studied by DNA sequencing of the penicillin-binding sites of the pbp1a, -2x, and -2b genes of strains and by determining 50% inhibitory concentrations of the seven agents for PBP1a, -2x, and -2b. Two PSSP strains had alterations in PBP2x (L546->V) (one strain) or PBP2b (T445->A) (one strain). All eight PISP strains had at least two alterations--T338->P or A or H394->Y in PBP2X and T445->A in BPB2b. All PRSP strains had the same changes seen in PISP strains, as well as T371->A or S substitutions in PBP1a. The two most resistant PRSP strains had a second change in PBP2x (M339->F) in a conserved motif. The affinities of penicillin and ampicillin for all three PBPs were decreased for PRSP and most PISP strains. The affinity of amoxicillin for PBP1a and -2x was decreased only for PRSP. Cefaclor and cefprozil showed decreased affinity of PRSP but not PISP for all three PBPs. Cefuroxime showed decreased affinity of PISP and PRSP for PBP1a and -2x but no change for PBP2b. Cefditoren showed no difference in PBP affinity based on penicillin or cefditoren MICs, indicating a different PBP target for this agent. Overall, the MICs for and PBP affinities of the strains correlated with the changes found in the PBP active binding sites.

* Corresponding author. Mailing address: 500 University Dr., Hershey, PA 17033. Phone: (717) 531-5113. Fax: (717) 531-7953. E-mail: pappelbaum{at}psu.edu.

Antimicrobial Agents and Chemotherapy, May 2002, p. 1273-1280, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1273-1280.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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