Colistin-resistant Acinetobacter baumannii

描述（由申请人提供）：鲍曼不动杆菌引起医院感染并对患者预后产生负面影响。鲍曼不动杆菌的特点是具有获得多药耐药性和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外的所有其他药物都具有耐药性。由这些微生物引起的感染可单独使用粘菌素（粘菌素的前药）或与另一种抗菌剂联合使用。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部分相互作用并引起膜的破坏。磷脂乙醇胺修饰脂质A被认为在鲍曼不动杆菌耐粘菌素中起关键作用。来自实验室产生的抗粘菌素突变株的研究结果表明，这种修饰带来了巨大的适应成本，并削弱了毒力。然而，一小部分耐粘菌素鲍曼不动杆菌患者会遭受长期感染和高死亡率。这表明耐粘菌素临床菌株具有其他机制，使它们能够在人类宿主中保持毒力并存活。我们收集了来自同一患者的成对粘菌素敏感和耐药的临床菌株，为我们提供了一个无与伦比的机会来定义耐药、适应性和毒力的临床相关机制，以及它们对耐粘菌素鲍曼不动杆菌的诊断和治疗的意义。需要验证的主要假设是：(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；(2)粘菌素耐药的适应性和毒性

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.