Staphylococcus aureus PBP4 is essential for beta-lactam resistance in community-acquired methicillin-resistant strains.
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 beta-lactams, does not play a role in the reduced resistance phenotype associated with the loss of PBP4. We also showed that cefoxitin, a semisynthetic beta-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.
Memmi
Guido
G
Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Filipe
Sergio R
SR
Pinho
Mariana G
MG
Fu
Zhibiao
Z
Cheung
Ambrose
A
D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002440:Cefoxitin / Q000008:administration & dosage; D017714:Community-Acquired Infections / Q000188:drug therapy* / Q000382:microbiology*; D017931:DNA Primers / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics; D004359:Drug Therapy, Combination; D017353:Gene Deletion; D005798:Genes, Bacterial; D005816:Genetic Complementation Test; D006801:Humans; D016106:Methicillin Resistance / Q000235:genetics; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D009154:Mutation; D046915:Penicillin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D010406:Penicillins / Q000008:administration & dosage; D010641:Phenotype; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology*; D018440:beta-Lactam Resistance / Q000235:genetics
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D017931:DNA Primers; D004269:DNA, Bacterial; D046915:Penicillin-Binding Proteins; D010406:Penicillins; C487789:mecA protein, Staphylococcus aureus; D002440:Cefoxitin