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Antimicrobial Agents and Chemotherapy, November 2008, p. 3955-3966, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00049-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Staphylococcus aureus PBP4 Is Essential for β-Lactam Resistance in Community-Acquired Methicillin-Resistant Strains{triangledown}

Guido Memmi,1 Sergio R. Filipe,2 Mariana G. Pinho,3 Zhibiao Fu,1 and Ambrose Cheung1*

Department of Microbiology, Dartmouth Medical School, Hanover, New Hampshire,1 Bacterial Cell Surfaces and Pathogenesis Laboratory,2 Bacterial Cell Biology Laboratory, Instituto de Tecnologia Química e Biológica, Oeiras, Portugal3

Received 14 January 2008/ Returned for modification 5 March 2008/ Accepted 20 August 2008

Recent cases of infections caused by community-acquired methicillin-resistant Staphylococcus aureus (MRSA) (CA-MRSA) strains in healthy individuals have raised concerns worldwide. CA-MRSA strains differ from hospital-acquired MRSAs by virtue of their genomic background and increased virulence in animal models. Here, we show that in two common CA-MRSA isolates, USA300 and MW2 (USA400), a loss of penicillin binding protein 4 (PBP4) is sufficient to cause a 16-fold reduction in oxacillin and nafcillin resistance, thus demonstrating that mecA, encoding PBP2A, is not the sole determinant of methicillin resistance in CA-MRSA. The loss of PBP4 was also found to severely affect the transcription of PBP2 in cells after challenge with oxacillin, thus leading to a significant decrease in peptidoglycan cross-linking. Autolysis, which is commonly associated with the killing mechanism of penicillin and β-lactams, does not play a role in the reduced resistance phenotype associated with the loss of PBP4. We also showed that cefoxitin, a semisynthetic β-lactam that binds irreversibly to PBP4, is synergistic with oxacillin in killing CA-MRSA strains, including clinical CA-MRSA isolates. Thus, PBP4 represents a major target for drug rediscovery against CA-MRSA, and a combination of cefoxitin and synthetic penicillins may be an effective therapy for CA-MRSA infections.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Dartmouth Medical School, Room 210, Vail Building, Hanover, NH 03755. Phone: (603) 650-1310. Fax: (603) 650-1318. E-mail: Ambrose.Cheung{at}Dartmouth.edu

{triangledown} Published ahead of print on 25 August 2008.

Antimicrobial Agents and Chemotherapy, November 2008, p. 3955-3966, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00049-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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