Role of Antimicrobial Resistance in Epidemic Clostridium difficile Infections

项目摘要 艰难梭菌引起严重的结肠炎疾病，导致每年数十亿美元的增加的 美国每年有超过20，000人死亡。在过去的十年里，一种流行病 已经出现了一种菌株（NAP 1/B1/核糖型027，毒素型III），其与 发病率和死亡率。C.艰难的“027”疫情感染者以惊人的速度增加 在过去的10年里，这些感染已经蔓延到全球。由这种菌株引起的感染治愈率较低 率和复发率高于其他C.艰难分离株。尽管 027流行性分离株的优势，我们不知道这个谱系的什么特性使快速流行性疾病成为可能。 这一系列的上升。本项目的长期目标是确定流行性分离的C。艰难 在宿主中增殖，从而可以确定预防和治疗感染的新方法。基于 根据我们的数据，我们假设C.因为它们能更成功地生存下来， 抗菌肽（AMP）的作用，使它们能够在肠道中更好地定植和复制。的 本申请的具体目的是鉴定027流行性C的遗传机制。难以赋予 增加宿主的AMP抗性。利用我们以前使用C的经验。难治性抗菌剂 肽抗性，我们将通过在两个具体目标中详述的实验来满足该目标。一是 将揭示流行性丙型肝炎AMP耐药的遗传机制。通过遗传分析的艰难菌株 AMP抗性缺陷的突变体。接下来，我们将确定AMP电阻的贡献 流行性分离物的定殖和感染机制。拟议方案的预期贡献 研究是鉴定027流行株C.艰难的，赋予增加 与非流行性菌株相比，抗微生物肽抗性。这一贡献意义重大，因为它是 了解027流行菌株抗菌肽耐药性增加的第一步 影响了这种重要病原体的传播

Project Summary 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 so 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.