Antimicrobial peptide resistance in Campylobacter jejuni

空肠弯曲杆菌的抗菌肽耐药性

基本信息

批准号：
7914369
负责人：
JUN LIN
金额：
$ 16.56万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7914369
关键词：
Animals Antibiotics Antimicrobial Resistance Bacteria Bacterial Infections Biochemical Biological Models Campylobacter Campylobacter coli Campylobacter infection Campylobacter jejuni Candidate Disease Gene Chickens Clinical Complex Defensins Development Domestic Fowls Exposure to Farming environment Food Safety Gastroenteritis Gene Silencing Genes Genetic Genome Goals Growth Host Defense Human In Vitro Intervention Intestines Knowledge Lead Meat Molecular Mutagenesis Natural Immunity Peptide Antibiotics Peptides Polymyxin B Population Predisposition Prevalence Public Health Research Resistance Resistance development Role Source Surface System Testing Therapeutic Effect United States Work antimicrobial peptide bactericide bacteriocin base cathelicidin commensal microbes effective intervention enteritis fitness foodborne foodborne pathogen functional genomics gastrointestinal genome wide association study in vivo insight killings mutant natural antimicrobial novel pathogen pressure prevent public health relevance research study resistance mechanism

项目摘要

DESCRIPTION (provided by applicant): Campylobacter jejuni is the leading bacterial cause of human enteritis in the United States. Contaminated poultry meats are considered a significant source for human Campylobacter infections. Increasing resistance of C. jejuni to clinical antibiotics poses a significant threat to public health and raises an urgent need for alternative strategies to prevent and control Campylobacter infections. Antimicrobial peptides (AMPs) are short and bactericidal peptides widely present in intestine to limit bacterial infections and also increasingly recognized as a novel class of antibiotics (peptide antibiotics) to control foodborne pathogens. Notably, several potent anti-Campylobacter bacteriocins, a group of AMPs produced by commensal bacteria, dramatically reduced C. jejuni colonization in chickens and are being directed toward on-farm control of this pathogen to protect public health. As an important strategy to evade killing by potential peptide antibiotics and by host innate defense, AMP resistance mechanisms in C. jejuni are critical to understand, but are still unknown. Our preliminary studies showed that Campylobacter could develop resistance to AMPs including the bacteriocins. We have also identified a panel of genes required for AMP resistance in C. jejuni using functional genomic approaches. Based on these observations, we hypothesize that Campylobacter has evolved complex mechanisms to develop AMP resistance and counteract killing by AMPs from various sources. To test our hypothesis, we plan to i) systematically identify and characterize genetic loci involved in C. jejuni resistance to AMPs using random transposon mutagenesis and whole genome microarray; and ii) determine the direct effect of therapeutic usage of bacteriocin on the emergence and persistence of bacteriocin-resistant Campylobacter using chicken model systems. It is anticipated that the proposed studies will enable us to develop more sustainable peptide antibiotics, provide insights into the delicate interplay between Campylobacter and the host, and ultimately lead to effective intervention strategies to prevent and control Campylobacter infections in humans. PUBLIC HEALTH RELEVANCE: Campylobacter jejuni is the most prevalent foodborne bacterial pathogen causing human gastroenteritis in the U.S. The proposed research will provide novel information on the development of effective intervention strategies against C. jejuni to protect food safety and public health.

描述（由申请人提供）：空肠弯曲杆菌是美国人类肠炎的主要原因。被污染的家禽肉被认为是人类弯曲杆菌感染的重要来源。越来越多的空肠对临床抗生素的抵抗力对公共卫生构成了重大威胁，并迫切需要采取预防和控制弯曲杆菌感染的替代策略。抗菌肽（AMP）是短的，杀菌肽广泛存在于肠道中，以限制细菌感染，并且越来越多地被认为是一种新型的抗生素（肽抗生素）来控制食源性病原体。值得注意的是，几种有效的抗抑制杆菌细菌，这是一组由共生细菌产生的AMP，大大降低了鸡的空肠梭菌结肠，并针对这种病原体的农业控制来保护公共卫生。作为逃避潜在肽抗生素杀死和宿主天生防御的重要策略，旋转梭菌的AMP耐药机制对于理解至关重要，但仍然未知。我们的初步研究表明，弯曲杆菌可以对包括细菌素在内的AMP产生抗性。我们还使用功能性基因组方法确定了在空肠梭菌中AMP抗性所需的基因。基于这些观察结果，我们假设弯曲杆菌已经发展出复杂的机制，从而发展了AMP抗性和抵抗来自各种来源的AMP的杀戮。为了检验我们的假设，我们计划i）使用随机的转座子诱变和整个基因组微阵列，系统地识别和表征与空肠梭状芽孢杆菌对AMPS抗药性有关的遗传基因座； ii）确定细菌素治疗用法对使用鸡模型系统的抗菌素抗弯曲杆菌的出现和持久性的直接作用。预计拟议的研究将使我们能够开发更多可持续的肽抗生素，为弯曲杆菌与宿主之间微妙的相互作用提供见解，并最终导致有效的干预策略，以预防和控制人类的弯曲杆菌感染。公共卫生相关性：空肠弯曲杆菌是美国最普遍的食源性细菌病原体，导致人类胃肠炎，拟议的研究将提供有关针对Jejuni的有效干预策略开发的新信息，以保护粮食安全和公共卫生。