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Antimicrobial Agents and Chemotherapy, February 2004, p. 453-459, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.453-459.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

PBP 2a Mutations Producing Very-High-Level Resistance to Beta-Lactams

Yuki Katayama, Hong-Zhong Zhang, and Henry F. Chambers*

Division of Infectious Diseases, San Francisco General Hospital, University of California, San Francisco, California

Received 31 May 2003/ Returned for modification 25 July 2003/ Accepted 8 October 2003

Resistance to the beta-lactam class of antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is mediated by PBP 2a, a synthetic bacterial cell wall penicillin-binding protein with a low affinity of binding to beta-lactams that is encoded by mecA. Beta-lactams that bind to PBP 2a with a high affinity and that are highly active against MRSA are under development. The potential for the emergence of resistance to such compounds was investigated by passage of homogeneous MRSA strain COL in L-695,256, an investigational carbapenem. A highly resistant mutant, COL52, expressed PBP 2a in which a two-amino-acid deletion mutation and three single-amino-acid substitution mutations were present. To examine the effects of these mutations on the resistance phenotype and PBP 2a production, plasmids carrying (i) PBP 2a with two or three of the four mutations, (ii) wild-type PBP 2a, or (iii) COL52 PBP 2a were introduced into methicillin-susceptible COL variants COLnex and COL52ex, from which the staphylococcus cassette chromosome mec (SCCmec) has been excised, as indicated by the "ex" suffix. Two amino acids substitutions, E->K237 within the non-penicillin-binding domain and V->E470 near the SDN464 conserved penicillin-binding motif in the penicillin-binding domain in COL52, were important for high-level resistance. The highest level of resistance was observed when all four mutations were present. The emergence of PBP 2a-mediated resistance to beta-lactams that bind to PBP 2a with a high affinity is likely to require multiple mutations in mecA; chromosomal mutations appear to have a minor role.

* Corresponding author. Mailing address: Infectious Diseases Laboratory/SFGH, Box 0811, 3rd and Parnassus Ave., San Francisco, CA 94143-0811. Phone: (415) 206-5437. Fax: (415) 648-8425. E-mail: chipc{at}itsa.ucsf.edu.

Antimicrobial Agents and Chemotherapy, February 2004, p. 453-459, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.453-459.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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