PBP1A Directly Interacts with the Divisome Complex to Promote Septal Peptidoglycan Synthesis in Acinetobacter baumannii.
PBP1A Directly Interacts with the Divisome Complex to Promote Septal Peptidoglycan Synthesis in Acinetobacter baumannii.
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DOI：
10.1128/jb.00239-22
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发表时间：
2022-12-20
影响因子：
3.2
通讯作者：
Boll, Joseph M.
中科院分区：
文献类型：
--
作者：
Kang, Katie N.;Boll, Joseph M.
关键词：
A类青霉素结合蛋白（aPBP）PBP 1A和PBP 1B是大肠杆菌中主要的肽聚糖降解酶，每代合成超过一半的肽聚糖。而aPBPs在生长期间的肽聚糖生物合成中具有不同的作用（即，伸长和分裂），它们是半冗余的;任何一个的破坏都被另一个拯救，以维持包膜的稳态并促进适当的生长。鲍曼不动杆菌是一种医院内病原体，具有克服抗菌治疗的高倾向。A.鲍曼不动杆菌含有PBP 1A和PBP 1B（分别由mrcA和mrcB编码），但只有mrcA缺失降低了适应性，并通过脂寡糖生物合成的失活而导致粘菌素抗性，表明PBP 1B与PBP 1A活性在功能上不是冗余的。虽然先前的研究表明PBP 1A在分裂中的独特作用，但尚不清楚其在间隔肽聚糖生物合成中的作用是否是直接的。在这里，我们表明，A.鲍曼不动杆菌PBP 1A通过与分裂体组分的相互作用在分裂中具有直接作用。PBP 1A在生长过程中定位于隔膜部位，在那里它与转肽酶PBP 3相互作用，转肽酶PBP 3是调节子细胞形成的必要分裂组分。PBP 3过表达足以挽救Δ mrcAA中的分裂缺陷。鲍曼不动杆菌;然而，当PBP 3被抑制时，PBP 1A过表达不足以挽救中隔缺损，这表明它们的活性不是多余的。一种主要的dd-carboxypeptidase，PBP 5的过表达，也恢复了典型的A。ΔmrcA细胞中的鲍曼不动杆菌形态。总之，这些数据支持PBP 1A在A.鲍曼不动杆菌分裂，并强调了其作为间隔肽聚糖合酶的作用。重要性肽聚糖生物合成是β-内酰胺类抗生素的有效靶点，了解多重耐药病原体（如鲍曼不动杆菌）的基本过程至关重要。虽然模型系统如大肠杆菌已经表明PBP 1A与侧壁肽聚糖合成有关，但我们在此表明A.鲍曼不动杆菌PBP 1A直接与分裂体组分PBP 3相互作用以促进分裂，表明该酶在这种高度耐药的医院病原体中具有独特的作用。A.鲍曼不动杆菌表现出对靶向抗生素的非预期的耐药性和耐受性，这可能是由肽聚糖机制的重新连接所驱动的，并且可能是抗生素治疗期间治疗失败的基础。
The class A penicillin-binding proteins (aPBPs), PBP1A and PBP1B, are major peptidoglycan synthases that synthesize more than half of the peptidoglycan per generation in Escherichia coli. Whereas aPBPs have distinct roles in peptidoglycan biosynthesis during growth (i.e., elongation and division), they are semiredundant; disruption of either is rescued by the other to maintain envelope homeostasis and promote proper growth. Acinetobacter baumannii is a nosocomial pathogen that has a high propensity to overcome antimicrobial treatment. A. baumannii contains both PBP1A and PBP1B (encoded by mrcA and mrcB, respectively), but only mrcA deletion decreased fitness and contributed to colistin resistance through inactivation of lipooligosaccharide biosynthesis, indicating that PBP1B was not functionally redundant with the PBP1A activity. While previous studies suggested a distinct role for PBP1A in division, it was unknown whether its role in septal peptidoglycan biosynthesis was direct. Here, we show that A. baumannii PBP1A has a direct role in division through interactions with divisome components. PBP1A localizes to septal sites during growth, where it interacts with the transpeptidase PBP3, an essential division component that regulates daughter cell formation. PBP3 overexpression was sufficient to rescue the division defect in ΔmrcA A. baumannii; however, PBP1A overexpression was not sufficient to rescue the septal defect when PBP3 was inhibited, suggesting that their activity is not redundant. Overexpression of a major dd-carboxypeptidase, PBP5, also restored the canonical A. baumannii coccobacilli morphology in ΔmrcA cells. Together, these data support a direct role for PBP1A in A. baumannii division and highlights its role as a septal peptidoglycan synthase. IMPORTANCE Peptidoglycan biosynthesis is a validated target of β-lactam antibiotics, and it is critical that we understand essential processes in multidrug-resistant pathogens such as Acinetobacter baumannii. While model systems such as Escherichia coli have shown that PBP1A is associated with side wall peptidoglycan synthesis, we show herein that A. baumannii PBP1A directly interacts with the divisome component PBP3 to promote division, suggesting a unique role for the enzyme in this highly drug-resistant nosocomial pathogen. A. baumannii demonstrated unanticipated resistance and tolerance to envelope-targeting antibiotics, which may be driven by rewired peptidoglycan machinery and may underlie therapeutic failure during antibiotic treatment.
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影响因子：
6.4
作者：
Boll JM;Hendrixson DR
通讯作者：
Hendrixson DR
影响因子：
6.4
作者：
Dai Y;Pinedo V;Tang AY;Cava F;Geisinger E
通讯作者：
Geisinger E
DOI：
10.1002/anie.201206749
发表时间：
2012-12-07
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Kuru E;Hughes HV;Brown PJ;Hall E;Tekkam S;Cava F;de Pedro MA;Brun YV;VanNieuwenhze MS
通讯作者：
VanNieuwenhze MS
DOI：
10.1073/pnas.1611594113
发表时间：
2016-10-11
影响因子：
11.1
作者：
Boll, Joseph M.;Crofts, Alexander A.;Trent, M. Stephen
通讯作者：
Trent, M. Stephen
影响因子：
2.1
作者：
Korsak, D;Vollmer, W;Markiewicz, Z
通讯作者：
Markiewicz, Z