The Penicillin-Binding Protein PbpP Is a Sensor of β-Lactams and Is Required for Activation of the Extracytoplasmic Function σ Factor σ P in Bacillus thuringiensis

β-Lactams are a class of antibiotics that target the synthesis of peptidoglycan, an essential component of the cell wall. β-Lactams inhibit the function of penicillin-binding proteins (PBPs), which form the cross-links between strands of peptidoglycan. Resistance to β-lactams complicates the treatment of bacterial infections. In recent years, the spread of β-lactam resistance has increased with growing intensity. Resistance is often conferred by β-lactamases, which inactivate β-lactams, or the expression of alternative β-lactam-resistant PBPs. σP is an extracytoplasmic function (ECF) σ factor that controls β-lactam resistance in the species Bacillus thuringiensis, Bacillus cereus, and Bacillus anthracis σP is normally held inactive by the anti-σ factor RsiP. σP is activated by β-lactams that trigger the proteolytic destruction of RsiP. Here, we identify the penicillin-binding protein PbpP and demonstrate its essential role in the activation of σP Our data show that PbpP is required for σP activation and RsiP degradation. Our data suggest that PbpP acts as a β-lactam sensor since the binding of a subset of β-lactams to PbpP is required for σP activation. We find that PbpP likely directly or indirectly controls site 1 cleavage of RsiP, which results in the degradation of RsiP and, thus, σP activation. σP activation results in increased expression of β-lactamases and, thus, increased β-lactam resistance. This work is the first report of a PBP acting as a sensor for β-lactams and controlling the activation of an ECF σ factor.IMPORTANCE The bacterial cell envelope is the target for numerous antibiotics. Many antibiotics target the synthesis of peptidoglycan, which is a central metabolic pathway essential for bacterial survival. One of the most important classes of antibiotics has been β-lactams, which inhibit the transpeptidase activity of penicillin-binding proteins to decrease the cross-linking of peptidoglycan and the strength of the cell wall. While β-lactam antibiotics have historically proven to be effective, resistance to β-lactams is a growing problem. The ECF σ factor σP is required for β-lactam resistance in B. thuringiensis and close relatives, including B. anthracis Here, we provide insight into the mechanism of activation of σP by β-lactams.