The Penicillin-Binding Protein PbpP Is a Sensor of β-Lactams and Is Required for Activation of the Extracytoplasmic Function σ Factor σ 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. σ is an extracytoplasmic function (ECF) σ factor that controls β-lactam resistance in the species , , and σ is normally held inactive by the anti-σ factor RsiP. σ 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 σ Our data show that PbpP is required for σ 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 σ activation. We find that PbpP likely directly or indirectly controls site 1 cleavage of RsiP, which results in the degradation of RsiP and, thus, σ activation. σ 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. 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 σ is required for β-lactam resistance in and close relatives, including Here, we provide insight into the mechanism of activation of σ by β-lactams.