Novel adjunctive therapy for drug resistant Gram-negative pathogens

描述(申请人提供)：越来越多的人认识到传染病的治疗面临着双重威胁。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。一组很有希望的化合物是阳离子宿主防御(抗微生物)肽，它们共同具有抗生物膜、抗微生物和免疫调节活性，几乎所有复杂的生物，从植物、昆虫到人类，都会自然产生，作为其天然防御感染的主要组成部分。我们的研究有助于将局部抗菌药和选择性免疫调节先天防御调节剂(IDR)肽输送到临床试验中；然而，这些试验并没有探索这些分子的全部潜力。最近，我们通过一些严重的革兰氏阴性细菌感染证明了其中一些多肽抑制生物膜的形成。在这里，我们将这一策略作为常规抗生素治疗的辅助手段。这一点特别重要，因为导致感染的细菌(60%)以生物膜的形式生长，这些生物膜是对传统抗生素高度耐药的专门殖民地结构。这里的目标是抑制高度耐药和危险的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缺乏新的抗生素发现的情况下，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，是为了(1)确定具有优化活性的更小且对蛋白酶具有抵抗力的多肽，(2)测试各种常规抗生素对生物被膜状态下的生物的协同作用，(3)了解抗生物被膜活性的机制(S)，以及(4)在真实的感染模型中表征它们的活性。1

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