Global Circuitry that Controls Acinetobacter Resistance and Virulence

控制不动杆菌耐药性和毒力的全球电路

• 批准号: 10651743
• 负责人: Edward Geisinger
• 金额: $ 39.18万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-26 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651743
• 关键词: Acinetobacter; Acinetobacter baumannii; Anabolism; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bypass; Cell Membrane Permeability; Cell physiology; Cells; Clinical; Data; Dedications; Defect; Dependence; Development; Disease; Drug resistance; Face; Failure; Gene Fusion; Genes; Goals; Growth; Healthcare; Heart; Homeostasis; Hospitals; Human; Immune; Immune Evasion; In Vitro; Infection; Innate Immune System; Knowledge; Lesion; Link; Membrane; Membrane Proteins; Microbe; Microbial Biofilms; Modeling; Multidrug-resistant Acinetobacter; Mus; Mutation; Names; Orthologous Gene; Pathogenicity; Pathway interactions; Patient Isolation; Patients; Penetration; Permeability; Pharmaceutical Preparations; Phospholipids; Phosphorylation; Predisposition; Production; Protein Biosynthesis; Proteins; Public Health; Regulation; Regulon; Reporter; Research; Resistance; Ribosomes; Sensory; Sepsis; Signal Transduction; Stress; Surface; System; Testing; Translational Repression; Treatment Failure; Variant; Virulence; Virulence Factors; Virulent; Work; addiction; antimicrobial; base; biological adaptation to stress; candidate identification; cell envelope; chemical genetics; drug resistant bacteria; drug resistant pathogen; env Gene Products; experimental study; extensive drug resistance; genetic regulatory protein; infection management; knock-down; member; microorganism; mortality; pathogen; promoter; response; therapeutic target; transposon sequencing

PROJECT SUMMARY Acinetobacter baumannii is among the most antibiotic-resistant pathogens known, and the emergence of isolates with enhanced virulence poses an urgent public health challenge. Understanding how the microorganism thwarts antibiotic and immune attack via its protective cell envelope is essential to developing new strategies for controlling this threat. Envelope synthesis and integrity in bacteria are typically maintained by a large number of response systems that control specific aspects of the envelope. A. baumannii, however, has diverged substantially from this paradigm. The pathogen lacks orthologs of many canonical envelope response proteins and instead relies on a single two-protein regulatory system to globally modulate every layer of the envelope and control both antibiotic resistance and ability to cause disease. This unique system, known as BfmRS, lowers susceptibility to a wide range of drugs, antagonizes innate immune killing, and facilitates development of lethal disease in mice. Intriguingly, a clinical isolate showing enhanced virulence requires the system for growth. BfmRS is therefore tightly linked to the intractability of infections with the pathogen and represents a key potential therapeutic target. Despite its fundamental importance, we lack an understanding of how the large BfmRS regulon controls broad- range drug resistance and pathogenicity, and what signals the system senses. The objective of the proposed studies is to understand how A. baumannii uses a single control circuit to simultaneously modulate resistance and virulence. Our central hypothesis is that BfmRS jointly controls the barrier to both drug penetration and innate immune attack by modulating the level of key outer membrane (OM) structures in response to disruptions in envelope protein production. We will test this hypothesis by pursuing three Aims, which build on our extensive preliminary data defining the BfmRS regulon and its chemical-genetic profile, as well as the phosphorylation cascade it uses for signaling. In Aim 1 we will test the model that BfmRS controls the bacterial interface with both antibiotics and innate immune effectors by modulating the OM barrier. In Aim 2, we will identify the antibiotic-induced and intrinsic stress signals that are sensed by BfmRS. In Aim 3, we will define the relationship between variability in BfmRS activity, growth-dependence, and virulence across diverse patient isolates as a test of the model that variation in BfmRS signaling level is a driver of enhanced virulence in invasive strains. This work will elucidate the mechanisms by which a unique regulatory system controls both resistance and pathogenicity in a critically important nosocomial microbe. These results will inform strategies for potentiating antibiotic and immune action for killing extensively drug-resistant bacteria.

项目摘要 鲍曼尼杆菌是已知的最抗生素的病原体之一，并且 具有增强毒力的分离株的出现构成了紧急的公共卫生挑战。理解 微生物如何通过其保护细胞包膜阻止抗生素和免疫攻击对 制定控制这种威胁的新策略。细菌的包膜合成和完整性是 通常由控制信封特定方面的大量响应系统维护。一个。 然而，鲍曼尼（Baumannii）与该范式有很大不同。病原体缺乏许多人的直系同源 规范的包膜反应蛋白，而依靠单个两蛋白调节系统 全球调节包膜的每一层，并控制抗生素耐药性和能力 引起疾病。这个被称为BFMR的独特系统降低了对多种药物的敏感性， 拮抗先天免疫杀戮，并促进小鼠致命疾病的发展。有趣的是， 临床分离株表现出增强的毒力需要增长系统。因此，BFMR紧密链接 感染与病原体的顽固性，代表了一个关键的潜在治疗靶点。尽管 它的基本重要性，我们对大型BFMRS统治如何控制广泛的理解缺乏了解 范围耐药性和致病性，以及系统感官的信号。目的 拟议的研究是了解A. Baumannii如何同时使用单个控制电路 调节电阻和毒力。我们的中心假设是BFMR共同控制了这两者的障碍 通过调节关键外膜（OM）结构的水平，药物渗透和先天免疫攻击 响应包膜蛋白产生的破坏。我们将通过追求三个来检验这一假设 目的，基于我们定义BFMRS Regulon及其化学生成的广泛初步数据 曲线以及它用于信号传导的磷酸化级联反应。在AIM 1中，我们将测试模型 BFMR通过调节抗生素和先天免疫效应子来控制细菌界面 OM障碍。在AIM 2中，我们将确定抗生素诱导的固有应力信号 BFMR。在AIM 3中，我们将定义BFMRS活动的变异性，增长依赖性， 以及各种患者分离株的毒力作为模型的测试，即BFMRS信号传导水平的变化为 侵入性菌株中毒力增强的驱动力。这项工作将阐明一种机制 独特的监管系统控制着非常重要的医院中的抗药性和致病性 微生物。这些结果将为增强抗生素和免疫作用的策略提供杀害的策略。 广泛的耐药细菌。

项目成果

A New Class of Cell Wall-Recycling l,d-Carboxypeptidase Determines β-Lactam Susceptibility and Morphogenesis in Acinetobacter baumannii.

• DOI: 10.1128/mbio.02786-21
• 发表时间: 2021-12-21
• 期刊: mBio
• 影响因子: 6.4
• 作者: Dai Y;Pinedo V;Tang AY;Cava F;Geisinger E
• 通讯作者: Geisinger E

Genome-wide phage susceptibility analysis in Acinetobacter baumannii reveals capsule modulation strategies that determine phage infectivity.

• DOI: 10.1371/journal.ppat.1010928
• 发表时间: 2023-06
• 期刊: PLoS pathogens
• 影响因子: 6.7

A conserved zinc-binding site in Acinetobacter baumannii PBP2 required for elongasome-directed bacterial cell shape.

• DOI: 10.1073/pnas.2215237120
• 发表时间: 2023-02-21
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Micelli, Carmina;Dai, Yunfei;Raustad, Nicole;Isberg, Ralph R.;Dowson, Christopher G.;Lloyd, Adrian J.;Geisinger, Edward;Crow, Allister;Roper, David I.
• 通讯作者: Roper, David I.