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

项目总结 背景：抗生素传统上被开发和部署为独立的抗菌剂， 构成了杀死微生物的单一破坏性压力。虽然最初是成功的，但这种模式呈现出 防止出现抵抗的最小障碍。因此，人类和微生物之间的军备竞赛已经 达到危险的临界点：许多具有临床意义的细菌病原体对 多种抗生素，在某些情况下是所有抗生素。近15年来，休斯实验室和 同事们研究了人类趋化因子CXCL10的抗微生物作用。这款多功能 效应器介导受体依赖的宿主靶向活动，包括免疫防御和再生 对多药耐药(MDR)细菌病原体具有直接杀菌作用。 为了利用这些行动的治疗效用，我们的合作团队将主要 CXCL10的生物活性：多肽P1发挥宿主靶向作用 多肽D8可杀死多种多药耐药细菌。我们假设这一令人兴奋的突破提供了 一种可调整的安排，从中平衡和应用直接杀死人的“多重”治疗策略 入侵细菌，利用免疫防御来对抗感染，促进宿主恢复。 方法：为了测试这个创新的概念，我们建议部署CXCL10衍生的多肽来对抗 伤口/手术部位感染，这是与医疗保健相关的最常见和最昂贵的感染类型。使用 建立了能够测量伤口愈合和感染结果的小鼠模型，我们将：[目标1] 区分多肽P1的剂量/剂量策略影响宿主免疫参与和促进 组织修复/再生；和[目的2]确定杀菌肽D8的治疗效果，无辅助 和多肽P1一起，对抗碳青霉烯耐药肠杆菌科细菌引起的伤口感染 (CRE)和耐甲氧西林金黄色葡萄球菌(MRSA)，临床挑战的病原体 人类的伤口感染。动物研究将通过详细阐述生理学的体外研究而得到丰富 和杀菌作用模式，测量多肽的生物稳定性，评估潜在的铅多肽细胞毒性，以及 评估抗多肽D8的细菌表型的出现。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公认的专业知识 传染病、再生医学、免疫疗法、多肽化学和治疗学发展。 结果：拟议的研究活动有望产生全新的抗感染和再生能力 技术，并建立一种独特的范式，使抗菌疗法不仅杀死病原体，而且 还征召宿主程序来抗击感染，使选择压力多样化，并促进恢复。 本申请中描述的原始资源和令人信服的初步数据证明了该方法的可行性和 在解决耐多药细菌日益沉重的负担方面成功实现这些结果的可能性。

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.