Role of Antimicrobial Resistance in Epidemic Clostridium difficile Infections

抗生素耐药性在流行性艰难梭菌感染中的作用

• 批准号: 8684103
• 负责人: SHONNA M. MCBRIDE
• 金额: $ 7.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684103
• 关键词: Affect; Animal Model; Antimicrobial Resistance; Bacteria; Bacterial Infections; Candidate Disease Gene; Cessation of life; Clostridium difficile; Cost of Illness; Data; Development; Digestive System Disorders; Disease; Environment; Epidemic; Future; Genes; Genetic; Goals; Growth; Health Care Costs; Host Defense; Incidence; Indigenous; Infection; Intestines; Investigation; Mission; Morbidity - disease rate; Pathogenesis; Pathway interactions; Peptides; Production; Proliferating; Property; Recurrent disease; Regulator Genes; Research; Resistance; Ribotypes; Ribotyping; Role; Testing; Toxin; United States; Virulence; antimicrobial peptide; base; design; experience; fitness; genetic analysis; killings; meetings; mortality; mutant; novel strategies; pandemic disease; pathogen; prevent; public health relevance; research study; resistance mechanism; theories

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.

项目概要 艰难梭菌会引起严重的腹泻病，导致每年增加数十亿美元的损失。 美国每年有超过 20,000 人死亡。近十年来，一场流行病 已出现菌株（NAP1/B1/核糖型 027，毒素型 III），该菌株与 发病率和死亡率。艰难梭菌“027”流行感染发病率增长惊人 在过去的十年里，这些感染已经在全球范围内蔓延。这种菌株引起的感染治愈率较低 与其他艰难梭菌分离株引起的感染相比，其发病率和复发率更高。尽管 027 流行分离株占优势，我们不知道该谱系的哪些特性使得该谱系能够迅速传播 这种应变的上升。该项目的长期目标是确定艰难梭菌的流行分离株如何 在宿主体内增殖，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，我们假设流行性艰难梭菌更普遍，因为它们更能成功生存 抗菌肽 (AMP) 的作用，使它们能够在肠道中更好地定植和复制。这 本申请的具体目标是确定 027 流行性艰难梭菌的遗传机制，这些机制赋予 宿主体内的 AMP 抵抗力增加。利用我们之前在艰难梭菌抗菌方面的经验 肽抗性，我们将通过两个具体目标中详述的实验来实现这一目标。首先，我们 将通过遗传分析揭示流行性艰难梭菌菌株AMP抗性的遗传机制 AMP 抗性缺陷的突变体。接下来，我们将确定 AMP 电阻的贡献 流行病分离株的定植和感染机制。拟议的预期贡献 研究目的是鉴定 027 艰难梭菌流行菌株的遗传机制，这些菌株可提高 与非流行菌株相比，抗菌肽耐药性。这一贡献意义重大，因为它 第一步了解027流行菌株抗菌肽耐药性如何增加 影响这种重要病原体的传播。