Role of Antimicrobial Resistance in Epidemic Clostridium difficile Infections

描述（由申请人提供）：艰难梭菌引起严重的腹泻疾病，每年在美国导致数十亿美元的医疗保健费用增加和超过20,000人死亡。在过去十年中，出现了一种流行毒株（NAP1/B1/核糖型027，毒素型III），与发病率和死亡率的显著增加有关。艰难梭菌“027”流行病感染的发病率在过去10年中以惊人的速度增加，这些感染已在全球蔓延。与其他难辨梭菌分离株引起的感染相比，这种菌株引起的感染治愈率较低，疾病复发率较高。尽管027流行分离株占主导地位，但我们不知道该谱系的哪些特性使该菌株能够迅速上升。该项目的长期目标是确定艰难梭菌的流行分离株如何在宿主中增殖，从而确定预防和治疗感染的新方法。根据我们的数据，我们假设流行病艰难梭菌更普遍，因为它们更成功地在抗菌肽（amp）的作用下存活，使它们能够更好地在肠道中定植和复制。本应用程序的具体目的是确定027流行病艰难梭菌中赋予宿主AMP抗性增加的遗传机制。利用我们以前在艰难梭菌抗微生物肽耐药性方面的经验，我们将

DESCRIPTION (provided by applicant): Clostridium difficile causes severe diarrheal disease that results in billions of dollars per year in increased health care costs and more than 20,000 deaths annually in the United States. In the past decade, an epidemic strain has emerged (NAP1/B1/ribotype 027, toxinotype III) that is associated with a significant increase in morbidity and mortality. The incidence of C. difficile "027" epidemic infections has increased at an alarming rate in the past 10 years and these infections have spread globally. Infections caused by this strain have lower cure rates and higher rates of relapsing disease than infections caused by other C. difficile isolates. Despite the predominance of 027 epidemic isolates, we do not know what properties of this lineage have enabled the rapid ascent of this strain. The long-term goal of this project is to determine how epidemic isolates of C. difficile proliferate in the host o that new approaches for preventing and treating infections can be identified. Based on our data, we hypothesize that epidemic C. difficile are more pervasive because they more successfully survive the effects of antimicrobial peptides (AMPs), allowing them to colonize and replicate better in the intestine. The specific objective of this application is to identify the genetic mechanisms in 027 epidemic C. difficile that confer increased AMP resistance in the host. Capitalizing on our previous experience with C. difficile antimicrobial peptide resistance, we will meet this objective through the experiments detailed in two specific aims. First, we will reveal the genetic mechanisms of AMP resistance in epidemic C. difficile strains through genetic analysis of mutants defective in AMP resistance. Next, we will determine the contribution of AMP resistance mechanisms to colonization and infection by epidemic isolates. The expected contribution of the proposed research is the identification of genetic mechanisms in 027 epidemic strains of C. difficile that confer increased antimicrobial peptide resistance compared to non-epidemic strains. This contribution is significant because it is the first step in understanding how the increased antimicrobial peptide resistance of 027 epidemic strains influences the spread of this important pathogen.