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

重塑抗生素模型的独特策略：针对宿主和病原体的趋化因子启发疗法，对抗多重耐药细菌引起的感染

• 批准号: 10676878
• 负责人: MOLLY A HUGHES
• 金额: $ 61.31万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676878
• 关键词: Address; Adoption; Affect; Amino Acids; Animal Experimentation; Anti-Infective Agents; Antibiotics; Antimicrobial Resistance; Area; Bacteria; Biological; Biological Process; Biology; CXCL10 gene; Cell physiology; Cells; Chemistry; Clinical; Clinical Management; Collection; Communicable Diseases; Data; Dermal; Development; Disease Progression; Dose; Equilibrium; Etiology; Exhibits; Foundations; Gram-Positive Bacteria; Health; Host Defense; Human; Immune; Immunotherapy; In Vitro; Individual; Infection; Injury; Intention; Invaded; Investigation; Klebsiella pneumoniae; Laboratories; Lead; Life; Measures; Mediating; Methodology; Microbe; Modeling; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mus; Natural regeneration; Outcome; Pattern; Peptide Hydrolases; Peptides; Periodicity; Phenotype; Physiological; Pneumonia; Process; Productivity; Recovery; Regenerative Medicine; Research; Research Activity; Resistance; Resources; Shapes; Surgical Wound Infection; System; Technology; Testing; Therapeutic; Treatment Efficacy; Wound Infection; antimicrobial; arms race; bacterial resistance; bactericide; cancer therapy; carbapenem-resistant Enterobacteriaceae; chemokine; clinically significant; combat; combat wound; combinatorial; cost; cytotoxicity; dosage; drug discovery; efficacy evaluation; fortification; healing; healthcare-associated infections; human pathogen; immune clearance; immunotoxicity; in vivo; in vivo regeneration; innovation; insight; lead series; man; methicillin resistant Staphylococcus aureus; microorganism; mortality; mouse model; multi-drug resistant pathogen; next generation; novel therapeutics; pathogen; pathogenic bacteria; pre-clinical; pressure; receptor; regenerative; therapeutic development; therapeutic target; tissue repair; usability; wound; wound bed; wound healing; wound treatment

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.

项目概要 背景：抗生素传统上是作为独立的抗菌剂开发和使用的， 包括杀死微生物的单一破坏性压力。虽然最初取得了成功，但该模型呈现出 防止耐药性出现的最小障碍。于是，人类与微生物之间的军备竞赛就这样展开了。 达到了危险的临界点：许多具有临床意义的细菌病原体对细菌的抵抗力越来越强 多种（在某些情况下）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 CXCL10 的抗菌作用。这款多功能 效应器介导受体依赖性宿主靶向活动，包括免疫防御和再生 过程以及对多重耐药 (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，我们的合作团队划分了主要的 将CXCL10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 可以杀死多种 MDR 细菌。我们假设这一令人兴奋的突破提供 一种可调的安排，从中平衡和应用直接杀死的“多重”治疗策略 入侵细菌，动员免疫防御来对抗感染，并促进宿主康复。 方法：为了测试这一创新概念，我们建议部署 CXCL10 衍生肽来对抗 伤口/手术部位感染是最常见且成本最高的医疗保健相关感染类型。使用 建立了适合测量伤口愈合和感染结果的小鼠模型，我们将：[目标 1] 区分影响宿主免疫参与和促进的肽 P1 剂量/剂量策略 组织修复/再生； [目标 2] 确定杀菌肽 D8 在无辅助条件下的治疗效果 与肽 P1 一起，对抗碳青霉烯类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），临床上具有挑战性的病原体 人类伤口感染。详细阐述生理学的体外研究将丰富动物研究 和杀菌作用模式，测量肽生物稳定性，评估潜在的先导肽细胞毒性，以及 评估肽 D8 抗性细菌表型的出现。拟议的研究将是 由在临床领域具有丰富专业知识的跨学科合作者小组完成 传染病、再生医学、免疫疗法、肽化学和疗法开发。 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，并建立独特的范例，使抗菌疗法不仅杀死病原体，而且 还征募宿主进程来对抗感染、分散选择性压力并促进恢复。 本申请中描述的原始资源和令人信服的初步数据证明了可行性和 成功实现这些成果以解决日益增加的耐多药细菌负担的可能性。

项目成果

The Pro-Inflammatory Chemokines CXCL9, CXCL10 and CXCL11 Are Upregulated Following SARS-CoV-2 Infection in an AKT-Dependent Manner.

SARS-CoV-2 感染后，促炎趋化因子 CXCL9、CXCL10 和 CXCL11 以 AKT 依赖性方式上调。

• 发表时间: 2021-06-03
• 作者: Callahan, Victoria;Hawks, Seth;Crawford, Matthew A;Lehman, Caitlin W;Morrison, Holly A;Ivester, Hannah M;Akhrymuk, Ivan;Boghdeh, Niloufar;Flor, Rafaela;Finkielstein, Carla V;Allen, Irving Coy;Weger;Duggal, Nisha;Hughes, Molly
• 通讯作者: Hughes, Molly