A unique strategy for reshaping the antibiotics model: chemokine-inspired therapeutics for targeting the host and pathogen to counter infections caused by multidrug-resistant bacteria

项目摘要 背景：抗生素传统上作为独立的抗微生物剂开发和使用， 包括单一的破坏性压力以杀死微生物。虽然最初取得了成功，但这种模式 最小限度地阻止抵抗的出现。因此，人类和微生物之间的军备竞赛 达到了一个危险的临界点：许多具有临床意义的细菌病原体对 多种，在某些情况下，所有可用的抗生素。近15年来，休斯实验室和 同事们研究了人类趋化因子CXCL 10的抗微生物作用。该多功能 效应子介导受体依赖性宿主靶向活动，包括免疫防御和再生 过程，以及对多药耐药（MDR）细菌病原体的直接杀菌作用。 为了利用这些行动的治疗效用，我们的合作团队将主要的 将CXCL 10的生物活性转化为一对单独定制的衍生物：肽P1发挥宿主靶向作用。 作用，而肽D8杀死不同的MDR细菌。我们假设这个令人兴奋的突破 一个可调的安排，从中平衡和应用“多重”治疗策略，直接杀死 入侵的细菌，争取免疫防御来对抗感染，并促进宿主恢复。 方法：为了测试这一创新概念，我们建议部署CXCL 10衍生肽来对抗 伤口/手术部位感染是最常见和最昂贵的医疗保健相关感染类型。使用 建立适合测量伤口愈合和感染结果的鼠模型，我们将：[目的1] 区分肽P1剂量/剂量策略，用于影响宿主免疫接合和促进 组织修复/再生;以及[目的2]确定杀菌肽D8的治疗功效， 并与肽P1一起对抗由碳青霉烯类耐药肠杆菌科引起的伤口感染 (CRE)和耐甲氧西林金黄色葡萄球菌（MRSA），临床上具有挑战性的病原体， 人类的伤口感染体外研究将丰富动物研究， 和杀菌作用模式，测量肽的生物稳定性，评估潜在的先导肽细胞毒性， 评估肽D8抗性细菌表型的出现。拟议的研究将是 由一个跨学科的合作者小组完成，他们在临床领域具有专业知识， 传染病、再生医学、免疫疗法、肽化学和治疗学开发。 结果：拟议的研究活动预计将产生全新的抗感染和再生药物。 技术，并建立一个独特的范例，使抗菌治疗不仅杀死病原体， 还可以动员东道国的进程来对抗感染、分散选择性压力和促进恢复。 本申请中描述的原始资源和令人信服的初步数据证明了 成功实现这些结果的可能性，以解决MDR细菌日益增加的负担。

PROJECT SUMMARY Background: Antibiotics have traditionally been developed and deployed as stand-alone antimicrobials, comprising a single destructive pressure to kill microorganisms. While initially successful, this model presents minimal barrier against the emergence of resistance. Thus, the arms race between man and microbe has reached a perilous tipping point: many clinically-significant bacterial pathogens are increasingly resistant to multiple, and in some cases all, available antibiotics. For nearly 15 years the Hughes laboratory and colleagues have investigated the antimicrobial actions of the human chemokine CXCL10. This multifunctional effector mediates receptor-dependent host-targeted activities, including immune defense and regenerative processes, as well as direct bactericidal effects against multidrug-resistant (MDR) bacterial pathogens. Towards harnessing the therapeutic utility of these actions, our collaborative team has divided the principal biological activities of CXCL10 into a pair of individually-tailored derivatives: peptide P1 exerts host-targeted effects, while peptide D8 kills diverse MDR bacteria. We hypothesize that this exciting breakthrough provides a tunable arrangement from which to balance and apply a 'multi-fold' therapeutic strategy that directly kills invading bacteria, enlists immune defense to combat infection, and promotes host recovery. Approach: To test this innovative concept, we propose to deploy CXCL10-derived peptides to counter wound/surgical site infections, the most common and costly type of healthcare-associated infection. Using an established murine model amenable to measuring wound healing and infection outcomes, we will: [Aim 1] distinguish peptide P1 dose/dosage strategies for affecting host-immune engagement and the promotion of tissue repair/regeneration; and [Aim 2] determine the therapeutic efficacy of bactericidal peptide D8, unaided and together with peptide P1, against wound infections caused by carbapenem-resistant Enterobacteriaceae (CRE) and methicillin-resistant Staphylococcus aureus (MRSA), clinically-challenging etiologic agents of wound infections in humans. Animal research will be enriched by in vitro studies that elaborate physiologic and bactericidal modes-of-action, measure peptide biostability, assess potential lead-peptide cytotoxicity, and evaluate the emergence of peptide D8-resistant bacterial phenotypes. The proposed research will be accomplished by a cross-disciplinary group of collaborators with demonstrated expertise in the areas of clinical infectious diseases, regenerative medicine, immunotherapy, peptide chemistry, and therapeutics development. Outcomes: The proposed research activities are expected to yield entirely new anti-infective and regenerative technologies, and establish a unique paradigm whereby antimicrobial therapies not only kill pathogens, but also conscript host processes to combat infection, diversify selective pressures, and promote recovery. The original resources and compelling preliminary data described in this application attest to the feasibility and likelihood of successfully achieving these outcomes towards addressing the mounting burden of MDR bacteria.