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

• 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
• 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

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）：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。一组有前景的化合物是阳离子宿主防御（抗菌）肽，它们共同具有抗生物膜，抗菌和免疫调节活性，并且几乎由从植物和昆虫到人类的所有复杂生物体天然产生，作为其先天防御感染的主要组成部分。我们的研究在局部抗菌剂和选择性免疫调节先天防御调节剂（IDR）肽的临床试验中发挥了重要作用；然而，这些试验并没有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了一些严重的革兰氏阴性细菌感染的生物膜的形成。在这里，我们正在追求这种策略作为传统抗生素治疗的辅助。这是特别相关的，因为引起感染的细菌通常（60%）以生物膜的形式生长，这种生物膜是一种特殊的群体结构，对传统抗生素具有高度耐药性。这里的目标是抑制高度耐药和危险病原体的生物膜感染，使这些感染更容易受到传统抗生素的影响。因此，我们的主要长期目标是在新抗生素发现匮乏的情况下，创造急需的治疗感染的新方法，以克服抗生素耐药性。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，对蛋白酶有抗性；(2)测试与各种传统抗生素在生物膜状态下的协同作用；(3)了解抗生物膜活性的机制；(4)在现实感染模型中表征它们的活性。1