Novel adjunctive therapy for drug 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 公共卫生相关性：抗生素时代，源于青霉素的部署，引入了可以说是有史以来最成功的药物，通过减少儿童和成人因感染而死亡，并使复杂的手术，移植和癌症化疗对预期寿命产生了巨大影响。由于多种抗生素耐药性的爆发和新抗生素发现率的下降，细菌感染性疾病的治疗现在受到严重威胁。该提案将通过开发新的策略和药物来应对耐药性革兰氏阴性病原体，直接解决这一严重的公共卫生问题。

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.