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结肠炎疾病，每年导致数十亿美元的医疗保健费用增加，每年在美国有超过20，000人死亡。在过去的十年中，出现了一种流行菌株（NAP 1/B1/ribotype 027，toxinotype III），与发病率和死亡率的显著增加有关。C.艰难梭菌“027”疫情感染在过去10年中以惊人的速度增加，并在全球范围内蔓延。由该菌株引起的感染比其他C.艰难分离株。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迅速上升。本项目的长期目标是确定流行性分离的C。艰难梭菌在宿主中增殖，从而可以鉴定用于预防和治疗感染的新方法。根据我们的数据，我们假设流行性C。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，使它们能够在肠道中更好地定殖和复制。本申请的具体目标是确定027流行C的遗传机制。在宿主中赋予增加的AMP抗性的艰难梭菌。利用我们以前使用C的经验。艰难的抗菌肽耐药性，我们将 通过在两个具体目标中详述的实验来实现这一目标。首先，我们将揭示流行性丙型肝炎中AMP耐药的遗传机制。艰难梭菌菌株通过AMP抗性缺陷突变体的遗传分析。接下来，我们将确定AMP耐药机制对流行性分离株定殖和感染的贡献。这项研究的预期贡献是确定027流行株C。与非流行性菌株相比，艰难梭菌赋予增加的抗微生物肽抗性。这一贡献意义重大，因为这是了解027流行菌株抗菌肽耐药性增加如何影响这一重要病原体传播的第一步。

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.