Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
mBio. 2021 Mar 23;12(2):e00179-21. doi: 10.1128/mBio.00179-21.
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.
β-内酰胺类抗生素是一类靶向肽聚糖合成的抗生素，肽聚糖是细胞壁的重要组成部分。β-内酰胺类抗生素抑制青霉素结合蛋白（PBPs）的功能，PBPs 形成肽聚糖链之间的交联。β-内酰胺类抗生素耐药性使细菌感染的治疗变得复杂。近年来，β-内酰胺类抗生素耐药性的传播呈加剧趋势。耐药性通常由β-内酰胺酶赋予，β-内酰胺酶使β-内酰胺类抗生素失活，或表达替代的β-内酰胺类耐药性 PBPs。σ 是一种细胞外功能（ECF）σ 因子，控制着 、 和 等物种中的 β-内酰胺类抗生素耐药性，σ 通常由抗 σ 因子 RsiP 保持失活。β-内酰胺类抗生素触发 RsiP 的蛋白水解破坏，从而激活 σ。在这里，我们鉴定了青霉素结合蛋白 PbpP，并证明了它在 σ 激活中的重要作用。我们的数据表明，PbpP 是 σ 激活和 RsiP 降解所必需的。我们的数据表明，PbpP 充当 β-内酰胺类抗生素的传感器，因为一组 β-内酰胺类抗生素与 PbpP 的结合是 σ 激活所必需的。我们发现 PbpP 可能直接或间接控制 RsiP 的位点 1 切割，导致 RsiP 的降解，从而激活 σ。σ 激活导致 β-内酰胺酶的表达增加，从而导致 β-内酰胺类抗生素耐药性增加。这项工作首次报道了一种 PBP 作为 β-内酰胺类抗生素的传感器，并控制 ECF σ 因子的激活。细菌细胞包膜是许多抗生素的靶标。许多抗生素针对肽聚糖的合成，肽聚糖是细菌生存所必需的中央代谢途径。最重要的抗生素之一是β-内酰胺类抗生素，它抑制青霉素结合蛋白的转肽酶活性，减少肽聚糖的交联和细胞壁的强度。虽然β-内酰胺类抗生素在历史上被证明是有效的，但β-内酰胺类抗生素耐药性是一个日益严重的问题。ECF σ 因子 σ 是 和近亲（包括 ）中 β-内酰胺类抗生素耐药性所必需的。在这里，我们提供了对 β-内酰胺类抗生素激活 σ 的机制的深入了解。
