Novel adjunctive therapy for drug resistant Gram-negative pathogens

耐药革兰氏阴性病原体的新型辅助治疗

基本信息

批准号：
8267449
负责人：
Robert Ernest William Hancock
金额：
$ 17.02万
依托单位：
UNIVERSITY OF BRITISH COLUMBIA
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：
2012-06-18 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267449
关键词：
Acinetobacter Acinetobacter baumannii Address Adjuvant Therapy Adult Animal Model Antibiotic Resistance Antibiotic Therapy Antibiotics Antiviral resistance Bacteria Biological Assay British Columbia Burkholderia CAP18 lipopolysaccharide-binding protein Campylobacter Canada Cells Cessation of life Chemotherapy-Oncologic Procedure Childhood Clinic Clinical Clinical Trials Collaborations Communicable Diseases Complex Computing Methodologies Data Dental Research Development Dissociation Drug resistance Enterobacter Escherichia coli O157 Explosion Genes Genetic Transcription Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Growth Host Defense Human In Vitro Infection Insecta Institutes Klebsiella Klebsiella pneumonia bacterium Life Expectancy Listeria monocytogenes Lung Medicine Membrane Methods Microbial Biofilms Modeling Multi-Drug Resistance Organ Transplantation Organism Penicillins Peptide Hydrolases Peptides Pharmaceutical Preparations Phase Plants Polymyxins Property Pseudomonas Pseudomonas aeruginosa Public Health Quantitative Structure-Activity Relationship RNA Research Resistance Salmonella Screening procedure Staging Structure System Testing Texas Therapeutic Time Toxic effect Trauma Research Twin Multiple Birth Universities Variant antimicrobial antimicrobial peptide base cell motility design in vivo mouse model natural antimicrobial novel novel strategies novel therapeutics pathogen preclinical study predictive modeling prevent quorum sensing stem surgical research synthetic peptide uptake

项目摘要

DESCRIPTION (provided by applicant): It is becoming increasingly recognized that the therapy of infectious diseases is facing twin threats. On the one hand antibiotic and antiviral resistance is rising rapidly; on the other there are relatively few novel compounds under development or entering the clinic. One promising set of compounds are the cationic host defense (antimicrobial) peptides, that collectively have anti-biofilm, antimicrobial and immunomodulatory activities and are naturally produced by virtually all complex organisms ranging from plants and insects to humans as a major component of their innate defenses against infection. Our research has been instrumental in delivering, to clinical trials, both topicl antimicrobials and selectively immunomodulatory innate defense regulator (IDR) peptides; however these trials did not explore the full potential of these molecules. Recently we demonstrated that some of these peptides suppress the formation of biofilms by a number of serious Gram negative bacterial infections. Here we are pursuing this strategy as an adjunct to conventional antibiotic therapy. It is particularly relevant since bacteria causing infections ofte (60%) grow as biofilms that are specialized colonial structures that are highly resistant to conventional antibiotics. The objective here is this to suppress biofilm infection by highly resistant and dangerous pathogens, making these infections more susceptible to conventional antibiotics. Our major broad long term objective is thus to create badly needed new approaches to treating infections to overcome antibiotic resistance in the face of a dearth in new antibiotic discovery. Our Specific Aims, in large part based on preliminary data, are (1) identify peptides with optimized activities that are smaller and resistant to proteases, (2) test synergy with a variety of conventional antibiotics against organisms in the biofilm state, (3) understand the mechanism(s) of anti-biofilm activity and (4) characterize their activity in realistic models of infection. 1 PUBLIC HEALTH RELEVANCE: The antibiotic era, stemming from the deployment of penicillin, introduced arguably the most successful medicine of all time, impacting dramatically on life expectancy by decreasing childhood and adult deaths from infections, and enabling complex surgeries, transplantations and cancer chemotherapy. The therapy of bacterial infectious diseases is now under severe threat due to an explosion of multiple antibiotic resistance, and a declining rate of discovery of new antibiotics. This proposal will directly address this serious public health issue by developing novel strategies and drugs to deal with recalcitrant resistant Gram-negative pathogens.

描述（由申请人提供）：越来越认识到传染病的治疗正面临双胞胎威胁。一方面，抗生素和抗病毒耐药性正在迅速上升。另一方面，正在开发或进入诊所的新型化合物相对较少。一组有希望的化合物是阳离子宿主防御（抗菌）肽，它们具有抗生物胶片，抗菌和免疫调节活性，并且自然是由植物和昆虫到人类作为其先天防御的主要组成部分的几乎所有复杂的生物体，它们是由植物和昆虫造成的。我们的研究对临床试验，主题抗菌剂和有选择的免疫调节的先天防御调节剂（IDR）肽发挥了作用。但是，这些试验并未探索这些分子的全部潜力。最近，我们证明了其中一些肽通过许多严重的革兰氏阴性细菌感染抑制了生物膜的形成。在这里，我们将这种策略作为常规抗生素疗法的辅助手段。它特别相关，因为引起感染的细菌（60％）会随着专门对常规抗生素具有高度耐药性的专业殖民结构而生长。这里的目的是通过高度抗性和危险的病原体抑制生物膜感染，使这些感染更容易受到常规抗生素的影响。因此，我们主要的长期长期目标是在面对新的抗生素发现的缺乏时创造出急需的新方法来治疗感染以克服抗生素耐药性。我们的特定目标在很大程度上是基于初步数据的，是（1）鉴定具有较小且对蛋白酶具有抗性的优化活动的肽，（2）测试与生物膜状态的各种常规抗生素测试协同作用，（3）了解抗生物膜活动的机制，并了解其抗生物性脂肪性活性和（4）的现实模型。 1 公共卫生相关性：抗生素时代是由于青霉素的部署而引入的，可以说是有史以来最成功的药物，通过减少感染的儿童和成人死亡，并启用复杂的手术，移植和癌症化学疗法，从而极大地影响了预期寿命。由于多种抗生素耐药性的爆炸以及新抗生素的发现率下降，细菌传染病的治疗现在正受到严重威胁。该提案将通过制定新的策略和药物来处理抗顽固性革兰氏阴性病原体，直接解决这一严重的公共卫生问题。