Function and inhibition of multidrug efflux systems in Campylobacter

弯曲杆菌多药外排系统的功能和抑制

• 批准号: 9005922
• 负责人: Qijing Zhang
• 金额: $ 37.04万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005922
• 关键词: 5 year old; Accounting; Address; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bile fluid; Biology; Campylobacter; Campylobacter infection; Campylobacter jejuni; Child; Chronic; Clinical Treatment; Coupled; Cysteine; DNA Binding; Development; Diarrhea; Disease; Drug resistance; Enteral; Family; Fluoroquinolones; Funding; Gene Expression; Genes; Goals; Health; In Vitro; Infection; Intestines; Irritable Bowel Syndrome; Laboratories; Macrolide Antibiotics; Macrolides; Mediating; Mutation; Organism; Oxidative Stress; Pathway interactions; Peptide Nucleic Acids; Physiological; Play; Poison; Prevalence; Public Health; Regulation; Repression; Research; Resistance; Role; Signal Transduction; Stress; System; Transcription Repressor/Corepressor; Vaccines; Work; antibiotic efflux; antimicrobial; base; biological adaptation to stress; combat; design; efflux pump; enteric pathogen; experience; fluoroquinolone resistance; in vivo Model; innovation; mortality; mutant; novel; novel strategies; pathogen; prevent; response; transmission process

 DESCRIPTION (provided by applicant): Campylobacter jejuni is a leading bacterial cause of diarrhea worldwide and is increasingly resistant to clinically important antibiotics. Among the known mechanisms involved in antibiotic resistance in Campylobacter, the multidrug efflux system CmeABC (an RND-type efflux transporter) is a significant player and confers resistance to structurally diverse antibiotics and toxic compounds. Additionally, CmeABC plays a critical role in bile resistance and is essential for Campylobacter colonization in the intestinal tract. Mot recently it was found that CosR, a response regulator for oxidative stress, serves as a repressor for cmeABC and modulates the expression of cmeABC in response to oxidative stress. These results strongly suggest that oxidative stress is a previously unidentified physiological signal modulating the function of CmeABC and the CosR-mediated response to oxidative stress may be important for the adaptation of C. jejuni, a microaerobic organism that experiences oxidative stress during transmission and infection of a host. Despite strong preliminary evidence, the detailed mechanisms of the interplay between oxidative stress and the CosR- CmeABC pathway and the role of this interaction in antibiotic and oxidative stress resistance are still unknown. To control antibiotic-resistant Campylobacter, we recently developed a novel strategy that utilizes anti-cmeABC peptide nucleic acid (PNA) to inhibit the expression of cmeABC. This approach was found to be effective in sensitizing Campylobacter to antibiotics, suggesting that antisense PNA targeting cmeABC is a promising approach for combating antibiotic-resistant Campylobacter. This application is based on these exciting findings and will pursue two Specific Aims i) to determine the mechanisms by which oxidative stress interacts with the CosR-CmeABC pathway and define the role of this interaction in Campylobacter adaptation to antibiotic and oxidative stresses, and ii) to determine the efficiency of anti-cmeABC PNA in preventing the emergence of antibiotic resistant mutants and potentiating antibiotics against Campylobacter in animal models. The proposal is innovative both conceptually and technically as it addresses an emerging theme at the interface between oxidative stress response and antibiotic efflux systems and develops a novel anti-Campylobacter approach by targeting CmeABC. The proposed work will significantly advance the concept that oxidative stress sensing and resistance is a common physiological function of antibiotic efflux systems in bacterial pathogens and will develop an effective mean to extend the utility of existing antibiotic against drug-resistant Campylobacter. Furthermore, the technical platform established in this project can be potentially adapted for the control of other antibiotic-resistant pathogens.

 描述（由申请人提供）：空肠弯曲菌是世界范围内引起腹泻的主要原因，并且对临床上重要的抗生素的耐药性日益增强，在弯曲杆菌抗生素耐药性的已知机制中，多药外排系统 CmeABC（一种 RND 型外排转运蛋白）。 CmeABC 是一个重要的参与者，赋予对结构多样的抗生素和有毒化合物的抗性，此外，CmeABC 在胆汁抵抗中发挥着关键作用，对于胆汁抵抗至关重要。最近，人们强烈发现 CosR（一种氧化应激反应调节剂）可作为 cmeABC 的抑制因子，并调节 cmeABC 的表达以应对氧化应激。调节 CmeABC 功能和 CosR 介导的氧化应激反应的未识别生理信号可能对于空肠弯曲菌的适应很重要，空肠弯曲菌是一种尽管有强有力的初步证据，但氧化应激与 CosR-CmeABC 途径之间相互作用的详细机制以及这种相互作用在抗生素和氧化应激抵抗中的作用仍然未知。为了控制抗生素耐药性弯曲杆菌，我们最近开发了一种新策略，利用抗 cmeABC 肽核酸 (PNA) 抑制 cmeABC 的表达，这种方法被发现是有效的。使弯曲杆菌对抗生素敏感，表明靶向 cmeABC 的反义 PNA 是对抗抗生素耐药弯曲杆菌的一种有前途的方法。该应用基于这些令人兴奋的发现，并将追求两个具体目标 i) 确定氧化应激与弯曲杆菌相互作用的机制。 CosR-CmeABC 途径并定义这种相互作用在弯曲杆菌适应抗生素和氧化应激中的作用，以及 ii) 确定anti-cmeABC PNA 在动物模型中防止抗生素耐药突变体的出现并增强抗生素对弯曲杆菌的抵抗力。该提案在概念和技术上都具有创新性，因为它解决了氧化应激反应和抗生素流出系统之间的一个新兴主题，并开发了一种新颖的方法。通过靶向 CmeABC 的抗弯曲杆菌方法将显着推进氧化应激传感和抵抗是细菌病原体中抗生素流出系统的常见生理功能的概念，并将发展这一概念。扩大现有抗生素针对耐药弯曲杆菌的效用的有效手段此外，该项目建立的技术平台可能适用于控制其他抗生素耐药病原体。