Antimicrobial peptide resistance in Campylobacter jejuni

描述（由申请人提供）：空肠弯曲杆菌是美国导致人类肠炎的主要细菌。受污染的禽肉被认为是人类弯曲杆菌感染的重要来源。空肠梭菌对临床抗生素的耐药性日益增强，对公共卫生构成重大威胁，迫切需要制定预防和控制弯曲杆菌感染的替代策略。抗菌肽（Antimicrobial peptides, AMPs）是广泛存在于肠道内的短肽，具有限制细菌感染的作用，也越来越被认为是一类控制食源性病原体的新型抗生素（肽类抗生素）。值得注意的是，几种有效的抗弯曲杆菌细菌素（一组由共生细菌产生的amp）显著减少了空肠梭菌在鸡体内的定植，并被用于农场控制这种病原体，以保护公众健康。作为逃避潜在肽抗生素和宿主先天防御的重要策略，AMP在空肠C. jejuni中的耐药机制亟待了解，但目前尚不清楚。我们的初步研究表明弯曲杆菌可以对抗菌肽产生耐药性，包括细菌素。我们还利用功能基因组方法确定了空肠C. AMP抗性所需的一组基因。基于这些观察结果，我们假设弯曲杆菌已经进化出复杂的机制来产生AMP抗性并抵抗来自各种来源的AMP的杀伤。为了验证我们的假设，我们计划i)利用随机转座子突变和全基因组微阵列技术系统地鉴定和表征空肠梭菌对AMPs抗性相关的遗传位点；ii)利用鸡模型系统确定治疗性使用细菌素对耐细菌素弯曲杆菌的出现和持续存在的直接影响。预计本研究将使我们能够开发更多可持续的肽抗生素，深入了解弯曲杆菌与宿主之间的微妙相互作用，并最终导致有效的干预策略，以预防和控制人类弯曲杆菌感染。公共卫生相关性：空肠弯曲杆菌是美国最常见的引起人类肠胃炎的食源性细菌病原体。拟议的研究将为开发有效的空肠弯曲杆菌干预策略提供新的信息，以保护食品安全和公众健康。

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.