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: 10468194
• 负责人: MOLLY A HUGHES
• 金额: $ 60.65万
• 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/10468194
• 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; Surgical Wound Infection; Surgical wound; System; Technology; Testing; Therapeutic; Treatment Efficacy; Wound Infection; antimicrobial; arms race; bacterial resistance; bactericide; base; cancer therapy; carbapenem-resistant Enterobacteriaceae; chemokine; clinically significant; combat; combat wound; combinatorial; cost; cytotoxicity; dosage; drug discovery; 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; 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.

项目摘要 背景：传统上已经开发并部署了抗生素，作为独立的抗生素， 包括单个破坏性压力以杀死微生物。虽然最初成功，但该模型提出了 抵抗出现的最小障碍。因此，人与微生物之间的武器竞赛 达到危险的临界点：许多临床上重要的细菌病原体对 多种，在某些情况下都是可用的抗生素。休斯实验室和 同事研究了人趋化因子CXCL10的抗菌作用。这个多功能 效应子介导受体依赖的宿主靶向活动，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，我们的合作团队分裂了校长 CXCL10的生物学活性成一对单独量化的衍生物：肽P1施加宿主目标 影响，而肽D8杀死了多种MDR细菌。我们假设这一令人兴奋的突破提供了 可调节的安排，可以平衡和采用直接杀死的“多重”治疗策略 入侵细菌，赋予免疫防御以对抗感染，并促进宿主恢复。 方法：为了测试这种创新概念，我们建议部署CXCL10衍生的肽来对抗 伤口/手术部位感染，这是医疗保健相关感染的最常见和昂贵类型。使用一个 已建立的鼠模型可用于测量伤口愈合和感染结果，我们将：[AIM 1] 区分肽P1剂量/剂量/剂量策略，以影响宿主免疫参与和促进 组织修复/再生； [AIM 2]确定杀菌肽D8的治疗功效 并与肽P1一起针对由碳苯甲酸肠杆菌引起的伤口感染 （CRE）和耐甲氧西林金黄色葡萄球菌（MRSA），临床挑战的病因学剂 人类伤口感染。动物研究将通过精心生理的体外研究丰富 和杀菌的作用模式，测量肽生物稳定性，评估潜在的铅肽细胞毒性和 评估肽D8耐药细菌表型的出现。拟议的研究将是 由跨学科的合作者组成的，在临床领域具有专业知识 传染病，再生医学，免疫疗法，肽化学和治疗剂开发。 结果：拟议的研究活动有望产生全新的反感染和再生 技术并建立独特的范式，抗菌疗法不仅杀死病原体，而且杀死病原体 还应应对宿主过程，以打击感染，多样化选择性压力并促进康复。 本应用程序中描述的原始资源和引人注目的初步数据证明了可行性和 成功实现这些结果来解决MDR细菌的负担的可能性。