This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Leski, T. A.
Right arrow Articles by Tomasz, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leski, T. A.
Right arrow Articles by Tomasz, A.

 Previous Article  |  Next Article 

Journal of Bacteriology, March 2005, p. 1815-1824, Vol. 187, No. 5
0021-9193/05/$08.00+0     doi:10.1128/JB.187.5.1815-1824.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Role of Penicillin-Binding Protein 2 (PBP2) in the Antibiotic Susceptibility and Cell Wall Cross-Linking of Staphylococcus aureus: Evidence for the Cooperative Functioning of PBP2, PBP4, and PBP2A

Tomasz A. Leski{dagger} and Alexander Tomasz*

The Rockefeller University, New York, New York1

Received 1 September 2004/ Accepted 19 November 2004

Ceftizoxime, a beta-lactam antibiotic with high selective affinity for penicillin-binding protein 2 (PBP2) of Staphylococcus aureus, was used to select a spontaneous resistant mutant of S. aureus strain 27s. The stable resistant mutant ZOX3 had an increased ceftizoxime MIC and a decreased affinity of its PBP2 for ceftizoxime and produced peptidoglycan in which the proportion of highly cross-linked muropeptides was reduced. The pbpB gene of ZOX3 carried a single C-to-T nucleotide substitution at nucleotide 1373, causing replacement of a proline with a leucine at amino acid residue 458 of the transpeptidase domain of the protein, close to the SFN conserved motif. Experimental proof that this point mutation was responsible for the drug-resistant phenotype, and also for the decreased PBP2 affinity and reduced cell wall cross-linking, was provided by allelic replacement experiments and site-directed mutagenesis. Disruption of pbpD, the structural gene of PBP4, in either the parental strain or the mutant caused a large decrease in the highly cross-linked muropeptide components of the cell wall and in the mutant caused a massive accumulation of muropeptide monomers as well. Disruption of pbpD also caused increased sensitivity to ceftizoxime in both the parental cells and the ZOX3 mutant, while introduction of the plasmid-borne mecA gene, the genetic determinant of the beta-lactam resistance protein PBP2A, had the opposite effects. The findings provide evidence for the cooperative functioning of two native S. aureus transpeptidases (PBP2 and PBP4) and an acquired transpeptidase (PBP2A) in staphylococcal cell wall biosynthesis and susceptibility to antimicrobial agents.

* Corresponding author. Mailing address: The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: (212) 327-8277. Fax: (212) 327-8688. E-mail: tomasz{at}rockefeller.edu.

{dagger} Present address: Chemistry Division, Naval Research Laboratory, Washington, D.C.

Journal of Bacteriology, March 2005, p. 1815-1824, Vol. 187, No. 5
0021-9193/05/$08.00+0     doi:10.1128/JB.187.5.1815-1824.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Beltramini, A. M., Mukhopadhyay, C. D., Pancholi, V. (2009). Modulation of Cell Wall Structure and Antimicrobial Susceptibility by a Staphylococcus aureus Eukaryote-Like Serine/Threonine Kinase and Phosphatase. Infect. Immun. 77: 1406-1416 [Abstract] [Full Text]  
  • Memmi, G., Filipe, S. R., Pinho, M. G., Fu, Z., Cheung, A. (2008). Staphylococcus aureus PBP4 Is Essential for {beta}-Lactam Resistance in Community-Acquired Methicillin-Resistant Strains. Antimicrob. Agents Chemother. 52: 3955-3966 [Abstract] [Full Text]  
  • Banerjee, R., Gretes, M., Basuino, L., Strynadka, N., Chambers, H. F. (2008). In Vitro Selection and Characterization of Ceftobiprole-Resistant Methicillin-Resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 52: 2089-2096 [Abstract] [Full Text]  
  • Fan, X., Liu, Y., Smith, D., Konermann, L., Siu, K. W. M., Golemi-Kotra, D. (2007). Diversity of Penicillin-binding Proteins: RESISTANCE FACTOR FmtA OF STAPHYLOCOCCUS AUREUS. J. Biol. Chem. 282: 35143-35152 [Abstract] [Full Text]  
  • Antignac, A., Sieradzki, K., Tomasz, A. (2007). Perturbation of Cell Wall Synthesis Suppresses Autolysis in Staphylococcus aureus: Evidence for Coregulation of Cell Wall Synthetic and Hydrolytic Enzymes. J. Bacteriol. 189: 7573-7580 [Abstract] [Full Text]  
  • Stapleton, P. D., Shah, S., Ehlert, K., Hara, Y., Taylor, P. W. (2007). The beta-lactam-resistance modifier (-)-epicatechin gallate alters the architecture of the cell wall of Staphylococcus aureus. Microbiology 153: 2093-2103 [Abstract] [Full Text]  
  • Pereira, S. F. F., Henriques, A. O., Pinho, M. G., de Lencastre, H., Tomasz, A. (2007). Role of PBP1 in Cell Division of Staphylococcus aureus. J. Bacteriol. 189: 3525-3531 [Abstract] [Full Text]  
  • Truong-Bolduc, Q. C., Hooper, D. C. (2007). The Transcriptional Regulators NorG and MgrA Modulate Resistance to both Quinolones and {beta}-Lactams in Staphylococcus aureus. J. Bacteriol. 189: 2996-3005 [Abstract] [Full Text]  
  • Nadarajah, J., Lee, M. J. S., Louie, L., Jacob, L., Simor, A. E., Louie, M., McGavin, M. J. (2006). Identification of different clonal complexes and diverse amino acid substitutions in penicillin-binding protein 2 (PBP2) associated with borderline oxacillin resistance in Canadian Staphylococcus aureus isolates.. J Med Microbiol 55: 1675-1683 [Abstract] [Full Text]  
  • Gardete, S., Wu, S. W., Gill, S., Tomasz, A. (2006). Role of VraSR in Antibiotic Resistance and Antibiotic-Induced Stress Response in Staphylococcus aureus.. Antimicrob. Agents Chemother. 50: 3424-3434 [Abstract] [Full Text]  
  • Gardete, S., de Lencastre, H., Tomasz, A. (2006). A link in transcription between the native pbpB and the acquired mecA gene in a strain of Staphylococcus aureus.. Microbiology 152: 2549-2558 [Abstract] [Full Text]  
  • Cooper, J. E., Feil, E. J. (2006). The phylogeny of Staphylococcus aureus - which genes make the best intra-species markers?. Microbiology 152: 1297-1305 [Abstract] [Full Text]  
  • Sobral, R. G., Ludovice, A. M., de Lencastre, H., Tomasz, A. (2006). Role of murF in Cell Wall Biosynthesis: Isolation and Characterization of a murF Conditional Mutant of Staphylococcus aureus.. J. Bacteriol. 188: 2543-2553 [Abstract] [Full Text]  
  • Matias, V. R. F., Beveridge, T. J. (2006). Native Cell Wall Organization Shown by Cryo-Electron Microscopy Confirms the Existence of a Periplasmic Space in Staphylococcus aureus. J. Bacteriol. 188: 1011-1021 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»