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: 8795713
• 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/8795713
• 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; 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; research study; resistance gene; resistance mechanism; theories

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.

描述（由申请人提供）：艰难梭菌会导致严重的腹泻病，导致美国每年增加数十亿美元的医疗保健费用，并导致 20,000 多人死亡。在过去的十年中，出现了一种流行毒株（NAP1/B1/核糖型 027，毒素型 III），其与发病率和死亡率的显着增加有关。过去10年中，艰难梭菌“027”流行性感染的发病率以惊人的速度增加，并且这些感染已在全球蔓延。与其他艰难梭菌分离株引起的感染相比，该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得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体内增殖，从而确定预防和治疗感染的新方法。根据我们的数据，我们假设流行性艰难梭菌更为普遍，因为它们能够更成功地在抗菌肽（AMP）的作用下存活下来，从而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 流行性艰难梭菌中赋予宿主 AMP 抗性增加的遗传机制。利用我们之前在艰难梭菌抗菌肽耐药性方面的经验，我们将 通过两个具体目标中详细说明的实验来实现这一目标。首先，我们将通过对AMP抗性缺陷突变体的遗传分析，揭示流行性艰难梭菌菌株AMP抗性的遗传机制。接下来，我们将确定 AMP 抗性机制对流行分离株定植和感染的贡献。拟议研究的预期贡献是鉴定 027 艰难梭菌流行菌株的遗传机制，与非流行菌株相比，这些菌株赋予抗菌肽耐药性增加。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种重要病原体传播的第一步。

项目成果

Synthetic polymers active against Clostridium difficile vegetative cell growth and spore outgrowth.

• DOI: 10.1021/ja506798e
• 发表时间: 2014-10-15
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Liu, Runhui;Suarez, Jose M.;Weisblum, Bernard;Gellman, Samuel H.;McBride, Shonna M.
• 通讯作者: McBride, Shonna M.