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Antimicrobial Agents and Chemotherapy, March 2009, p. 1107-1115, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01107-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

An Important Site in PBP2x of Penicillin-Resistant Clinical Isolates of Streptococcus pneumoniae: Mutational Analysis of Thr338{triangledown}

Ilka Zerfaß, Regine Hakenbeck,* and Dalia Denapaite

Department of Microbiology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany

Received 18 August 2008/ Returned for modification 28 September 2008/ Accepted 7 December 2008

Penicillin-binding protein 2x (PBP2x) of Streptococcus pneumoniae represents a primary resistance determinant for beta-lactams, and low-affinity PBP2x variants can easily be selected with cefotaxime. Penicillin-resistant clinical isolates of S. pneumoniae frequently contain in their mosaic PBP2x the mutation T338A adjacent to the active site S337, and T338P as well as T338G substitutions are also known. Site-directed mutagenesis has now documented that a single point mutation at position T338 confers selectable levels of beta-lactam resistance preferentially to oxacillin. Despite the moderate impact on beta-lactam susceptibility, the function of the PBP2x mutants appears to be impaired, as can be documented in the absence of a functional CiaRH regulatory system, resulting in growth defects and morphological changes. The combination of low-affinity PBP2x and PBP1a encoded by mosaic genes is known to result in high cefotaxime resistance. In contrast, introduction of a mosaic pbp1a into the PBP2xT338G mutant did not lead to increased resistance. However, the mosaic PBP1a gene apparently complemented the PBP2xT338G defect, since Cia mutant derivatives grew normally. The data support the view that PBP2x and PBP1a interact with each other on some level and that alterations of both PBPs in resistant clinical isolates have evolved to ensure cooperation between both proteins.

* Corresponding author. Mailing address: University of Kaiserslautern, Department of Microbiology, Paul Ehrlich Straße 23, D-67663 Kaiserslautern, Germany. Phone: 49 631 205 2353. Fax: 49 631 205 3799. E-mail: hakenb{at}rhrk.uni-kl.de

{triangledown} Published ahead of print on 15 December 2008.

Antimicrobial Agents and Chemotherapy, March 2009, p. 1107-1115, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01107-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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