Colistin-resistant Acinetobacter baumannii

粘菌素耐药鲍曼不动杆菌

• 批准号: 8629030
• 负责人: Yohei Doi
• 金额: $ 37.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629030
• 关键词: Acinetobacter baumannii; Affect; Antibiotics; Attenuated; Biological Assay; Biology; Carbapenems; Caring; Clinical; Colistin; Collection; Communicable Diseases; DNA Sequence Rearrangement; Diagnosis; Diagnostic; Epidemiology; Genomics; High-Throughput Nucleotide Sequencing; Hospitals; Human; In Vitro; Individual; Infection; K-Series Research Career Programs; Laboratory Finding; Left; Lipid A; Lipopolysaccharides; Membrane; Modeling; Modification; Multi-Drug Resistance; Mus; Nosocomial Infections; Nucleotides; Operon; Organism; Outcome; Patients; Physicians; Play; Process; Prodrugs; Proteome; Proteomics; Research Personnel; Resistance; Resistance development; Role; Societies; Staging; Structure; Testing; Vancomycin; Variant; Virulence; Virulent; Work; antimicrobial; antimicrobial drug; carbapenem resistance; clinically relevant; colistin resistance; cost; fitness; improved; in vitro Assay; in vivo; in vivo Model; insertion/deletion mutation; mortality; mutant; novel; novel diagnostics; novel therapeutic intervention; pathogen; phosphoethanolamine; public health relevance; rapid diagnosis; resistance mechanism; resistant strain

DESCRIPTION (provided by applicant): Acinetobacter baumannii causes hospital infections and negatively impacting patient outcome. A. baumannii is characterized by its exceptional ability to acquire multidrug resistance and spread among hospitalized patients. The rate of resistance to carbapenems in A. baumannii has now exceeded 40% in the U.S. Carbapenem- resistant strains are frequently resistant to all other agents except colistin. Infections due to these organisms are treated with colistimethate (prodrug of colistin) alone or in combination with another antimicrobial agent. However, the increased use of colistin has resulted in the emergence of colistin-resistant A. baumannii. Colistin interacts with the lipid A moiety of lipopolysaccharide and causes disorganization of the membrane. Modification of lipid A with phosphoethanolamine has been proposed as playing a key role in colistin resistance in A. baumannii. Findings from laboratory-generated colistin-resistant mutant strains suggest that this modification carries substantial fitness cost and impairs virulence. However, a subset of patients with colistin- resistant A. baumannii suffer prolonged infection and high mortality. This suggests that colistin-resistant clinical strains have additional mechanisms, which enable them to remain virulent and survive in the human hosts. Our collection of paired colistin-susceptible and -resistant clinical strains from same patients provides us with an unparalleled opportunity to define clinically relevant mechanisms of resistance, fitness and virulence, and their implications for the diagnosis and treatment of colistin-resistant A. baumannii. The central hypotheses to be tested are: (1) lipid A modification is the predominant mechanism of resistance to colistin and can be exploited for rapid diagnosis of resistance, (2) fitness and virulence of colistin-resistant A. baumannii is variable and dependent on the specific mechanism of resistance, and (3) combinations of antimicrobial agents have unique activity against colistin-resistant A. baumannii. To test these hypotheses, we plan to conduct the following Specific Aims: (1) Elucidate the lipid A structures associated with colistin resistance, (2) Characterize the fitness and virulence potential of colistin-resistant A. baumannii and the activity of antimicrobial combinations in in vitro and in vivo models, and (3) Define the genomic and proteomic correlates of colistin resistance. In addition to the existing colistin-resistant clinical strains,those collected prospectively from three hospitals with diverse epidemiology will also be studied, enhancing the generalizability of the findings. The study aims to elucidate the mechanisms of colistin resistance in A. baumannii that are relevant to clinical settings using a multifaceted yet integrated approach. The findings will substantially enhance our understanding of the biology of colistin-resistant A. baumannii, and contribute in devising both novel diagnostic and therapeutic approaches to improve the care of severely ill patients affected by this otherwise untreatable organism.

描述（由申请人提供）：鲍曼不动杆菌会引起医院感染并对患者的治疗结果产生负面影响。鲍曼不动杆菌的特点是具有获得多重耐药性并在住院患者中传播的特殊能力。在美国，鲍曼不动杆菌对碳青霉烯类药物的耐药率现已超过 40%。碳青霉烯类耐药菌株通常对除粘菌素以外的所有其他药物均具有耐药性。由这些微生物引起的感染可以单独使用粘菌素（粘菌素的前药）或与另一种抗菌剂联合治疗。然而，粘菌素使用的增加导致了耐粘菌素鲍曼不动杆菌的出现。粘菌素与脂多糖的脂质 A 部分相互作用并导致膜解体。已提出用磷酸乙醇胺修饰脂质 A 在鲍曼不动杆菌的粘菌素抗性中发挥关键作用。实验室产生的粘菌素抗性突变株的研究结果表明，这种修饰会带来巨大的适应性成本并削弱毒力。然而，一部分患有粘菌素耐药鲍曼不动杆菌的患者遭受长期感染和高死亡率。这表明耐粘菌素的临床菌株具有额外的机制，使它们能够保持毒力并在人类宿主中生存。我们从同一患者收集的配对的粘菌素敏感和耐药临床菌株为我们提供了无与伦比的机会来定义临床相关的耐药性、适应性和毒力机制，及其对粘菌素耐药鲍曼不动杆菌的诊断和治疗的影响。要测试的中心假设是：(1) 脂质 A 修饰是粘菌素耐药的主要机制，可用于快速诊断耐药性，(2) 粘菌素耐药的适应性和毒力 鲍曼不动杆菌是可变的，并且取决于特定的耐药机制，并且（3）抗菌药物的组合对粘菌素耐药的鲍曼不动杆菌具有独特的活性。为了检验这些假设，我们计划实现以下具体目标：（1）阐明与粘菌素耐药性相关的脂质 A 结构，（2）表征粘菌素耐药鲍曼不动杆菌的适应性和毒力潜力以及体外和体内模型中抗菌组合的活性，以及​​（3）定义粘菌素耐药性的基因组和蛋白质组相关性。除了现有的粘菌素耐药临床菌株外，还将对从具有不同流行病学特征的三家医院前瞻性收集的菌株进行研究，以增强研究结果的普遍性。该研究旨在利用多方面的方法阐明鲍曼不动杆菌的粘菌素耐药机制，这些机制与临床环境相关。 综合方法。这些发现将大大增强我们对耐粘菌素鲍曼不动杆菌生物学的理解，并有助于设计新的诊断和治疗方法，以改善受这种无法治疗的微生物影响的重症患者的护理。