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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：
8491975
负责人：
Robert Ernest William Hancock
金额：
$ 12.63万
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8491975
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 Research Resistance Salmonella 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 screening stem surgical research synthetic peptide transcriptome sequencing 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

描述（由申请人提供）：人们越来越认识到，传染病的治疗正面临双重威胁。一方面，抗生素和抗病毒药物的耐药性正在迅速上升;另一方面，正在开发或进入临床的新化合物相对较少。一组有前途的化合物是阳离子宿主防御（抗微生物）肽，其共同具有抗生物膜、抗微生物和免疫调节活性，并且由从植物和昆虫到人类的几乎所有复杂生物体天然产生，作为其对感染的先天防御的主要组分。我们的研究有助于将局部抗菌剂和选择性免疫调节性先天防御调节因子（IDR）肽交付临床试验;然而，这些试验并未探索这些分子的全部潜力。最近，我们证明了这些肽中的一些抑制由许多严重的革兰氏阴性细菌感染形成的生物膜。在这里，我们正在寻求这种策略作为常规抗生素治疗的辅助手段。这是特别相关的，因为引起感染的细菌通常（60%）作为生物膜生长，生物膜是对常规抗生素具有高度抗性的专门的菌落结构。其目的是抑制高耐药和危险病原体的生物膜感染，使这些感染对常规抗生素更敏感。因此，我们主要的广泛的长期目标是创造急需的新方法来治疗感染，以克服抗生素耐药性，面对缺乏新的抗生素发现。我们的具体目标，在很大程度上基于初步数据，是（1）鉴定具有优化活性的肽，这些肽更小且对蛋白酶具有抗性，（2）测试与各种常规抗生素对生物膜状态下的生物体的协同作用，（3）了解抗生物膜活性的机制，（4）在现实的感染模型中表征其活性。1

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Peptide design for antimicrobial and immunomodulatory applications.

DOI：
10.1002/bip.22250
发表时间：
2013-11
期刊：
BIOPOLYMERS
影响因子：
2.9
作者：
Haney, Evan F.;Hancock, Robert E. W.
通讯作者：
Hancock, Robert E. W.

Broad-spectrum anti-biofilm peptide that targets a cellular stress response.

针对细胞应激反应的广谱抗生物膜肽。

DOI：
10.1371/journal.ppat.1004152
发表时间：
2014-05
期刊：
PLoS pathogens
影响因子：
6.7
作者：
de la Fuente-Núñez C;Reffuveille F;Haney EF;Straus SK;Hancock RE
通讯作者：
Hancock RE

Current Research Approaches to Target Biofilm Infections.

当前针对生物膜感染的研究方法。

DOI：
10.14304/surya.jpr.v3n6.5
发表时间：
2015
期刊：
Postdoc journal : a journal of postdoctoral research and postdoctoral affairs
影响因子：
0
作者：
vanTilburgBernardes,Erik;Lewenza,Shawn;Reckseidler-Zenteno,Shauna
通讯作者：
Reckseidler-Zenteno,Shauna

Treatment of Oral Multispecies Biofilms by an Anti-Biofilm Peptide.

DOI：
10.1371/journal.pone.0132512
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Wang Z;de la Fuente-Núñez C;Shen Y;Haapasalo M;Hancock RE
通讯作者：
Hancock RE

Anti-Biofilm and Immunomodulatory Activities of Peptides That Inhibit Biofilms Formed by Pathogens Isolated from Cystic Fibrosis Patients.

DOI：
10.3390/antibiotics3040509
发表时间：
2014
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
0
作者：
de la Fuente-Núñez C;Mansour SC;Wang Z;Jiang L;Breidenstein EB;Elliott M;Reffuveille F;Speert DP;Reckseidler-Zenteno SL;Shen Y;Haapasalo M;Hancock RE
通讯作者：
Hancock RE