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Infection and Immunity, April 2009, p. 1406-1416, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.01499-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Modulation of Cell Wall Structure and Antimicrobial Susceptibility by a Staphylococcus aureus Eukaryote-Like Serine/Threonine Kinase and Phosphatase{triangledown}

Amanda M. Beltramini,1,3 Chitrangada D. Mukhopadhyay,2,3 and Vijay Pancholi2,3*

Integrated Biomedical Graduate Program,1 Department of Pathology,2 Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio 432103

Received 9 December 2008/ Returned for modification 19 January 2009/ Accepted 22 January 2009

It is well established that prokaryotes and eukaryotes alike utilize phosphotransfer to regulate cellular functions. One method by which this occurs is via eukaryote-like serine/threonine kinase (ESTK)- and phosphatase (ESTP)-regulated pathways. The role of these enzymes in Staphylococcus aureus has not yet been examined. This resilient organism is a common cause of hospital-acquired and community-associated infections, infecting immunocompromised and immunocompetent hosts alike. In this study, we have characterized a major functional ESTK (STK) and ESTP (STP) in S. aureus and found them to be critical modulators of cell wall structure and susceptibility to cell wall-acting β-lactam antibiotics. By utilizing gene knockout strategies, we created S. aureus N315 mutants lacking STP and/or STK. The strain lacking both STP and STK displayed notable cell division defects, including multiple and incomplete septa, bulging, and irregular cell size, as observed by transmission electron microscopy. Mutants lacking STP alone displayed thickened cell walls and increased resistance to the peptidoglycan-targeting glycylglycine endopeptidase lysostaphin, compared to the wild type. Additionally, mutant strains lacking STK or both STK and STP displayed increased sensitivity to cell wall-acting cephalosporin and carbapenem antibiotics. Together, these results indicate that S. aureus STK- and STP-mediated reversible phosphorylation reactions play a critical role in proper cell wall architecture, and thus the modulation of antimicrobial resistance, in S. aureus.

* Corresponding author. Mailing address: Department of Pathology, The Ohio State University, 288 Tzagournis Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210. Phone: (614) 688-8053. Fax: (614) 688-3192. E-mail: vijay.pancholi{at}osumc.edu

{triangledown} Published ahead of print on 2 February 2009.

Editor: A. Camilli

Infection and Immunity, April 2009, p. 1406-1416, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.01499-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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