Antimicrobial peptide resistance in Campylobacter jejuni

描述(申请人提供)：空肠弯曲杆菌是美国人类肠炎的主要细菌来源。受污染的禽肉被认为是人类弯曲杆菌感染的重要来源。空肠弯曲菌对临床抗生素的耐药性日益增加，对公众健康构成严重威胁，迫切需要替代策略来预防和控制弯曲杆菌感染。抗菌肽是一类广泛存在于肠道中的短小杀菌肽，用来限制细菌感染，也是一类越来越被公认的控制食源性致病菌的新型抗生素(多肽抗生素)。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，极大地减少了空肠弯曲菌在鸡中的定植，并正被用于农场控制这种病原体，以保护公众健康。空肠弯曲菌AMP耐药机制作为逃避潜在多肽抗生素和宿主天然防御的重要策略，其耐药机制目前尚不清楚。我们的初步研究表明，弯曲杆菌可以对包括细菌素在内的AMPs产生抗药性。我们还利用功能基因组学方法鉴定了空肠弯曲菌抗AMP所需的一组基因。基于这些观察，我们假设弯曲杆菌已经进化出复杂的机制来发展AMP抗性和对抗来自不同来源的AMP的杀戮。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系统地鉴定和表征空肠弯曲菌对AMPS耐药的遗传位点；ii)使用鸡模型系统确定细菌素治疗用药对耐细菌素弯曲杆菌的出现和持续的直接影响。预计拟议的研究将使我们能够开发更可持续的多肽抗生素，为了解弯曲杆菌与宿主之间的微妙相互作用提供见解，并最终导致有效的干预策略来预防和控制人类弯曲杆菌感染。与公共卫生相关：空肠弯曲杆菌是美国最常见的引起人类胃肠炎的食源性致病菌。这项拟议的研究将为开发有效的干预策略来保护食品安全和公众健康提供新的信息。

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.