Novel adjunctive therapy for drug resistant Gram-negative pathogens

人们越来越认识到，传染病的治疗正面临着双重威胁。上 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化合物。一组有前途的化合物是阳离子主体 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作用， 活动和自然产生的几乎所有复杂的生物体，从植物和昆虫， 人类作为其先天防御感染的主要组成部分。我们的研究对 在临床试验中，局部抗菌剂和选择性免疫调节先天防御 这些试验是针对IDR调节肽进行的;然而，这些试验没有探索这些分子的全部潜力。最近我们 表明，这些肽抑制生物膜的形成，由一些严重的革兰氏阴性菌， 阴性细菌感染。在这里，我们正在寻求这种策略作为常规抗生素的辅助手段 疗法这是特别相关的，因为引起感染的细菌通常（60%）生长为生物膜， 对常规抗生素具有高度抗性的专门的殖民结构。 这里的目的是抑制高抗性和危险病原体的生物膜感染， 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 创造急需的新方法来治疗感染，以克服抗生素耐药性， 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）确定具有优化活性的肽 较小且对蛋白酶具有抗性，（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）了解抗生物膜活性的机制和（4）表征 它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.