Staphylococci are the most common cause of bacterial infections in hospitalized patients (1). These spherical Gram-positive bacteria persist in hospitals because they acquire genes that render them resistant to most clinically useful antibiotics, including the β-lactams (penicillins and cephalosporins). The bacterial targets of β-lactam antibiotics are transpeptidase enzymes (penicillin-binding proteins) that maintain the structural integrity of the bacterial polysaccharide cell wall. Staphylococci resist attack by β-lactam antibiotics in two ways: They produce β-lactamases, enzymes that inactivate the β-lactam antibiotics, and they make new transpeptidase targets that are impervious to antibiotic activity. The signaling pathway that regulates production of β-lactamases has been studied for more than 30 years. On page 1962 of this issue, Zhang et al.(2) fill in several blanks in this pathway with their finding that production of β-lactamase depends on serial proteolytic cleavage of several key signaling components.

There are two genes that render staphylococci resistant to antibiotics—blaZ encoding β-lactamase and mecA encoding the penicillin binding protein PBP2a, which binds to β-lactam antibiotics with low affinity. These two genes and their regulators are transported on mobile elements acquired from other bacteria, and an extensive evolutionary relationship exists between them. Transcription of blaZ and mecA is regulated by the sensor-transducer proteins, BlaR1 and MecR1, and their partner repressors, BlaI and MecI, which bind to DNA sequences in the two genes.