Department of Microbiology, Cornell University, Ithaca, New York, USA.
Department of Host Microbe Interactions, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
J Bacteriol. 2024 Mar 21;206(3):e0001524. doi: 10.1128/jb.00015-24. Epub 2024 Feb 7.
Antibiotics that inhibit peptidoglycan synthesis trigger the activation of both specific and general protective responses. σ responds to diverse antibiotics that inhibit cell wall synthesis. Here, we demonstrate that cell wall-inhibiting drugs, such as bacitracin and cefuroxime, induce the σ-dependent operon. YtpA is a predicted hydrolase previously proposed to generate the putative lysophospholipid antibiotic bacilysocin (lysophosphatidylglycerol), and YtpB is the branchpoint enzyme for the synthesis of membrane-localized C terpenoids. Using targeted lipidomics, we reveal that YtpA is not required for the production of lysophosphatidylglycerol. Nevertheless, was critical for growth in a mutant strain defective for homeoviscous adaptation due to a lack of genes for the synthesis of branched chain fatty acids and the Des phospholipid desaturase. Consistently, overexpression of increased membrane fluidity as monitored by fluorescence anisotropy. The gene contributes to bacitracin resistance in mutants additionally lacking the or genes, which directly mediate bacitracin resistance. These epistatic interactions support a model in which σ-dependent induction of the operon helps cells tolerate bacitracin stress, either by facilitating the flipping of the undecaprenyl phosphate carrier lipid or by impacting the assembly or function of membrane-associated complexes involved in cell wall homeostasis.IMPORTANCEPeptidoglycan synthesis inhibitors include some of our most important antibiotics. In , peptidoglycan synthesis inhibitors induce the σ regulon, which is critical for intrinsic antibiotic resistance. The σ-dependent operon encodes a predicted hydrolase (YtpA) and the enzyme that initiates the synthesis of C terpenoids (YtpB). Our results suggest that YtpA is critical in cells defective in homeoviscous adaptation. Furthermore, we find that YtpA functions cooperatively with the BceAB and BcrC proteins in conferring intrinsic resistance to bacitracin, a peptide antibiotic that binds tightly to the undecaprenyl-pyrophosphate lipid carrier that sustains peptidoglycan synthesis.
抗生素抑制肽聚糖合成会引发特定和一般保护反应的激活。σ 响应多种抑制细胞壁合成的抗生素。在这里，我们证明细胞壁抑制药物，如杆菌肽和头孢呋辛，诱导 σ 依赖性 operon。YtpA 是一种先前被预测为产生假定的溶血磷脂抗生素 bacilysocin（溶血磷脂酰甘油）的水解酶，而 YtpB 是合成膜定位的 C 萜烯的分支点酶。通过靶向脂质组学，我们揭示 YtpA 不是产生溶血磷脂酰甘油所必需的。然而， 在由于缺乏合成支链脂肪酸和 Des 磷脂脱饱和酶的基因而导致同源粘弹性适应缺陷的突变菌株中，对于生长至关重要。一致地，荧光各向异性监测表明， 过表达增加了膜流动性。 基因对于缺乏 或 基因的突变体中的杆菌肽抗性很重要，这两个基因直接介导杆菌肽抗性。这些上位相互作用支持了这样一种模型，即 σ 依赖性诱导 operon 有助于细胞耐受杆菌肽应激，要么通过促进十一烯基磷酸载体脂质的翻转，要么通过影响与细胞壁稳态相关的膜相关复合物的组装或功能。
肽聚糖合成抑制剂包括我们一些最重要的抗生素。在 中，肽聚糖合成抑制剂诱导σ 调控子，这对于固有抗生素抗性至关重要。σ 依赖性 operon 编码一种预测的水解酶（YtpA）和起始 C 萜烯合成的酶（YtpB）。我们的结果表明，YtpA 在同源粘弹性适应缺陷的细胞中是至关重要的。此外，我们发现 YtpA 与 BceAB 和 BcrC 蛋白在赋予对杆菌肽的固有抗性方面协同作用，杆菌肽是一种紧密结合维持肽聚糖合成的十一烯基焦磷酸脂质载体的肽抗生素。
