Novel adjunctive therapy for drug resistant Gram-negative pathogens

越来越多的人认识到，传染病的治疗面临着双重威胁。论 一方面，抗生素和抗病毒耐药性正在迅速上升；另一方面，新药相对较少 正在开发或进入临床的化合物。一组很有希望的化合物是阳离子主体。 具有抗生物被膜、抗微生物和免疫调节功能的防御(抗微生物)多肽 它是由几乎所有复杂的生物体自然产生的，从植物和昆虫到 人类作为其抵抗感染的先天防御系统的主要组成部分。我们的研究是有益的 在为临床试验提供局部抗菌药和选择性免疫调节先天防御方面 调节(IDR)多肽；然而，这些试验并没有探索这些分子的全部潜力。最近我们 证明其中一些多肽通过一些严重的革兰氏菌抑制生物膜的形成 阴性细菌感染。在这里，我们将这一策略作为常规抗生素的补充。 心理治疗。这一点特别重要，因为引起感染的细菌通常(60%)是以生物膜的形式生长的 对常规抗生素高度耐药的专门化殖民地结构。 这里的目标是抑制高度耐药和危险的病原体对生物膜的感染，使 这些感染对常规抗生素更敏感。因此，我们的主要长远目标是 创造急需的新方法来治疗感染，以克服面对 缺乏新的抗生素发现。 我们的具体目标，在很大程度上是基于初步数据，是(1)确定具有最佳活性的多肽 较小且对蛋白酶有抵抗力的，(2)测试与各种常规抗生素的协同作用 生物膜状态下的生物，(3)了解抗生物膜的作用机制(S)和(4)表征 他们在真实的感染模型中的活动。

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 defence (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 defences against infection. Our research has been instrumental in delivering, to clinical trials, both topical antimicrobials and selectively immunomodulatory innate defence 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 often (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.