Potentiating antibiotics against Campylobacter by inhibiting efflux

通过抑制外流增强抗生素对抗弯曲杆菌的作用

基本信息

批准号：
8267838
负责人：
Qijing Zhang
金额：
$ 18.82万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267838
关键词：
Acute Address Animal Model Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Autoimmune Diseases Campylobacter Campylobacter infection Campylobacter jejuni Categories Cells Clinical Clinical Treatment Country Culture Media Development Drug Efflux Drug resistance Effectiveness Fluoroquinolones Gastroenteritis Gastrointestinal tract structure Goals Guillain-Barré Syndrome Human In Vitro Infection Infection Control Intestines Laboratories Macrolide Antibiotics Macrolides Measures Methodology National Institute of Allergy and Infectious Disease Paralysed Peptide Hydrolases Peptide Nucleic Acids Peptides Permeability Phase Play Poison Prevalence Public Health Regulation Repression Resistance Role System United States Vaccines Work antimicrobial combat design efflux pump enteric pathogen enteritis fluoroquinolone resistance improved in vivo mutant neuromuscular new technology novel novel strategies pathogen pressure prevent therapy development

项目摘要

DESCRIPTION (provided by applicant): Campylobacter jejuni is a major enteric pathogen and is responsible for a large number of gastroenteritis worldwide. Clinical treatment of campylobacteriosis requires the use of fluoroquinolone or macrolide antibiotics, but antibiotic-resistant Campylobacter is increasingly prevalent, compromising the effectiveness of antibiotic therapy. Novel strategies are urgently needed to control infections caused by antibiotic-resistant Campylobacter. Among the various mechanisms utilized by Campylobacter for antibiotic resistance, the CmeABC multidrug efflux pump is a critical and predominant player in the resistance to a wide range of antimicrobials and toxic compounds. This efflux system also plays an important role in facilitating the emergence of fluoroquinolone-resistant mutants from susceptible Campylobacter under antibiotic selection. To develop novel measures to combat antibiotic-resistant Campylobacter, we have initiated studies to explore the feasibility of using antisense Peptide Nucleic Acid (PNA) to target CmeABC. Our preliminary result suggests that the antisense PNA approach has a strong potential to inhibit the expression of cmeABC and sensitize Campylobacter to antibiotics. In this application, we will further develop and evaluate the antisense PNA approach as an adjunctive therapy for antibiotic-resistant Campylobacter. The Specific aim for the R21 phase is to develop and evaluate anti-CmeABC PNAs that effectively potentiate antibiotics against antimicrobial-resistant Campylobacter and the specific aims for the R33 phase are to assess the feasibility of using anti-CmeABC PNAs as an adjunctive therapy to combat antibiotic-resistant Campylobacter in an animal model, determine the efficiency of PNAs in preventing the emergence of fluoroquinolone-resistant mutants from susceptible Campylobacter, and improve the permeability and stability of PNAs by modifying cell-penetrating peptides. The proposed work takes advantage of a novel target (CmeABC) and a novel technology (antisense PNA) and utilizes both in vitro and in vivo methodologies. Once completed, the project will have developed an effective mean to extend the utility of existing antibiotics against drug-resistant Campylobacter. Furthermore, the technical platform established in this project can be potentially adapted for other antibiotic-resistant pathogens. Thus the work will not only significantly advance the discovery of novel adjunctive therapies for antibiotic-resistant Campylobacter, but also potentially benefit the development of therapy for other pathogens. PUBLIC HEALTH RELEVANCE: Campylobacter jejuni is a major enteric pathogen causing gastroenteritis in humans. Prevalence of antibiotic resistance in Campylobacter has become a major concern for public health. This project will significantly advance the discovery of adjunctive therapies that will extend the utility of existing antibiotics in treating infections cased by resistant Campylobacter.

描述（由申请人提供）：空肠弯曲菌是一种主要的肠道病原体，是全世界大量胃肠炎的罪魁祸首。弯曲杆菌病的临床治疗需要使用氟喹诺酮类或大环内酯类抗生素，但抗生素耐药弯曲杆菌日益普遍，损害了抗生素治疗的有效性。迫切需要新的策略来控制抗生素耐药弯曲杆菌引起的感染。在弯曲杆菌用于抗生素耐药性的各种机制中，CmeABC 多药外排泵是对多种抗菌药物和有毒化合物产生耐药性的关键和主要参与者。这种外排系统在抗生素选择下促进易感弯曲杆菌产生氟喹诺酮抗性突变体方面也发挥着重要作用。为了开发对抗抗生素耐药弯曲杆菌的新措施，我们已启动研究探索使用反义肽核酸 (PNA) 靶向 CmeABC 的可行性。我们的初步结果表明，反义 PNA 方法具有抑制 cmeABC 表达并使弯曲杆菌对抗生素敏感的强大潜力。在此应用中，我们将进一步开发和评估反义 PNA 方法作为抗生素耐药弯曲杆菌的辅助疗法。 R21 阶段的具体目标是开发和评估抗 CmeABC PNA，可有效增强抗生素对抗耐药弯曲杆菌的能力，R33 阶段的具体目标是评估使用抗 CmeABC PNA 作为辅助疗法来对抗耐药弯曲杆菌的可行性。动物模型中的抗生素耐药弯曲杆菌，确定 PNA 在防止易感弯曲杆菌中出现氟喹诺酮耐药突变体的效率，并提高渗透性和稳定性通过修饰细胞穿透肽来修饰 PNA。拟议的工作利用了新靶点 (CmeABC) 和新技术（反义 PNA），并利用了体外和体内方法。一旦完成，该项目将开发出一种有效的方法来扩展现有抗生素对抗耐药弯曲杆菌的效用。此外，该项目建立的技术平台有可能适用于其他抗生素耐药病原体。因此，这项工作不仅将显着推进针对抗生素耐药弯曲杆菌的新型辅助疗法的发现，而且还可能有利于其他病原体疗法的开发。公共卫生相关性：空肠弯曲菌是引起人类胃肠炎的主要肠道病原体。弯曲杆菌抗生素耐药性的普遍存在已成为公众健康的主要关注点。该项目将显着推进辅助疗法的发现，从而扩展现有抗生素在治疗耐药弯曲杆菌感染方面的效用。