Colistin-resistant Acinetobacter baumannii

描述(由申请人提供)：鲍曼不动杆菌会引起医院感染，并对患者预后产生负面影响。鲍曼不动杆菌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抗生素的耐药率已超过40%。耐碳青霉烯类抗生素的菌株通常对除粘菌素以外的所有其他药物耐药。由这些微生物引起的感染可单独或与另一种抗菌剂联合使用氨甲菌酯(粘菌素前体药物)治疗。然而，粘菌素使用的增加导致了对粘菌素耐药鲍曼不动杆菌的出现。粘菌素与脂多糖中的脂类A部分相互作用，导致细胞膜的破坏。磷乙醇胺修饰A脂在鲍曼不动杆菌粘菌素抗性中起关键作用。实验室产生的粘菌素抗性突变株的发现表明，这种修饰带来了相当大的适应成本，并削弱了毒力。然而，一部分对粘菌素耐药的鲍曼不动杆菌患者遭受长期感染和高死亡率。这表明粘菌素耐药临床菌株有额外的机制，使它们能够保持毒力并在人类宿主中生存。我们收集了来自同一患者的一对粘菌素敏感和耐药临床菌株，为我们提供了一个无与伦比的机会来确定临床相关的耐药性、适应性和毒力机制，以及它们对粘菌素耐药鲍曼不动杆菌的诊断和治疗的意义。需要检验的中心假设是：(1)脂质A修饰是粘菌素耐药性的主要机制，可用于快速诊断耐药性；(2)粘菌素耐药性的适合性和毒力 鲍曼不动杆菌是可变的，并依赖于特定的耐药机制，(3)抗菌药物组合对粘菌素耐药鲍曼不动杆菌具有独特的活性。为了验证这些假说，我们计划进行以下具体目标：(1)阐明与粘菌素耐药性相关的脂类A结构；(2)表征粘菌素耐药鲍曼不动杆菌的适合性和毒力潜力以及体外和体内模型中抗菌药物组合的活性；以及(3)确定粘菌素耐药性的基因组和蛋白质组相关性。除了现有的对粘菌素耐药的临床菌株外，还将研究那些预期从三家流行病学不同的医院收集的菌株，以增强研究结果的普遍性。本研究旨在通过多方面的研究阐明鲍曼不动杆菌粘菌素耐药的机制。 综合方法。这些发现将大大提高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，以改善受这种原本无法治疗的微生物影响的重病患者的护理。

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.