A Proteolytic Transmembrane Signaling Pathway and Resistance to β-Lactams in Staphylococci

β-Lactamase and penicillin-binding protein 2a mediate staphylococcal resistance to β-lactam antibiotics, which are otherwise highly clinically effective. Production of these inducible proteins is regulated by a signal-transducing integral membrane protein and a transcriptional repressor. The signal transducer is a fusion protein with penicillin-binding and zinc metalloprotease domains. The signal for protein expression is transmitted by site-specific proteolytic cleavage of both the transducer, which autoactivates, and the repressor, which is inactivated, unblocking gene transcription. Compounds that disrupt this regulatory pathway could restore the activity of β-lactam antibiotics against drug-resistant strains of Staphylococci.