Strategies to Block Skin Wound Infection by Intercepting Bacterial Cell-to-Cell Signaling

通过拦截细菌细胞间信号传导来阻止皮肤伤口感染的策略

• 批准号: 10667239
• 负责人: Helen E. Blackwell
• 金额: $ 22.33万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667239
• 关键词: Abscess; Address; Adhesions; Affect; Animal Model; Animals; Anti-Infective Agents; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Attenuated; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Biological; Bolus Infusion; Caring; Cause of Death; Cell Density; Cells; Chemical Agents; Chemicals; Clinical; Clinical Microbiology; Development; Disease; Distress; Dose; Drug Delivery Systems; Etiology; Explosion; Growth; Health; Hospitals; Host Defense Mechanism; Human; Immune Evasion; Infection; Infection Control; Infectious Skin Diseases; Intercept; Investigation; Knowledge; Lead; Medical; Methods; Microbial Biofilms; Modeling; Mus; Outcome; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Polymers; Process; Production; Protocols documentation; Reporting; Research; Rewards; Risk; Route; Signal Pathway; Signal Transduction; Staphylococcus aureus; Staphylococcus aureus infection; Testing; Thick; Time; Toxin; Treatment Cost; Validation; Virulence; Work; Wound Infection; bacterial resistance; biodegradable polymer; cell growth; controlled release; design; experience; experimental study; healing; human model; in vivo; in vivo Model; infancy; inhibitor; innovation; intercellular communication; interest; mouse model; novel; novel strategies; particle; pathogen; pathogenic bacteria; prevent; quorum sensing; resistance mechanism; skin wound; synergism; wound; wound bed

PROJECT SUMMARY This R21 project will use potent chemical inhibitors of bacterial cell-to-cell signaling to develop new materials and explore innovative approaches to prevent bacterial infections in skin wounds. Skin wound infections cause suffering and distress in over 6 million patients and incur treatment costs totaling over $25 billion annually in the US. The current arsenal of drugs available to treat these infections is now almost completely depleted due to the rise of bacterial resistance. Fundamentally new ‘anti-virulence’ approaches that move beyond conventional antibiotic strategies and target bacterial virulence rather than cell growth could provide means to address this threat and have major impacts on medical care. This current proposal seeks to develop such an approach by targeting a chemical signaling pathway—quorum sensing (QS)—that controls virulence in many of the antibiotic resistant bacteria common to skin wounds, including Staphylococcus aureus. QS in bacteria has emerged as an attractive target in the anti-virulence field because it controls many of the primary mechanisms that underlie bacterial infection, including toxin production, adhesion, immune evasion, and biofilm formation. These processes can have widespread and devastating effects on human health. Many pathogenic bacteria utilize QS to launch synchronized attacks on their hosts only after they have achieved a high cell density, thereby overwhelming the host’s defense mechanisms. Synthetic molecules capable of blocking QS represent a direct approach to inhibit bacterial virulence. Interest in such QS inhibitors (QSIs) has exploded over the past 20 years, but characterization of the activities of QSIs in vivo remains in its infancy. The in vivo studies to date have relied on either (i) QSIs with poor potency, unknown mechanisms, and/or off-target effects; or (ii) animal infection models that, while easy to perform, are not highly relevant to typical skin wound infection. New compounds, methods, and models are required to push the QS field forward. This R21 project will leverage a QSI recently developed by the PI—the most potent QSI to be reported—to advance new approaches and materials to block S. aureus wound infections. These objectives will be accomplished by the pursuit of two Aims: (1) investigation of the ability of the QSI to attenuate S. aureus infections in a well-tested mouse model of skin wound infection, and (2) characterization of combinations of the QSI with current antibiotics to explore synergies and enhance bacterial clearance in wound infections. Both Aims will integrate sustained release strategies using degradable polymers to explore and define optimal delivery approaches for the use of QSIs in wounds. Our investigations will be led by an expert team with >15 years of collective collaborative experience and unite the PI’s synthetic QSIs with the expertise of the Co-Is in materials-based drug delivery approaches, clinical microbiology, and animal models of wound infection. The outcomes of this project will significantly expand the understanding of bacterial QS in an animal model relevant to human wound infection and provide critical validation for QS inhibition as a route to ameliorate disease.

项目摘要 该R21项目将使用细菌细胞到细胞信号的潜在化学抑制剂开发新的 材料并探索创新方法，以防止皮肤伤口中的细菌感染。皮肤 伤口感染会导致超过600万患者的痛苦和困扰，并产生总计的治疗费用 每年在美国250亿美元。目前可用于治疗这些感染的药物的库现在几乎是 从根本上讲，新的“反病毒”方法 超越常规的抗生素策略和靶向细菌病毒而不是细胞生长可能 提供解决这一威胁并对医疗保健产生重大影响的手段。目前的提议试图 通过靶向化学信号通路（QUS）（QS）来开发这种方法 在包括金黄色葡萄球菌在内的许多抗生素耐药细菌中的毒力。 细菌中的QS已成为抗病毒场中的一个有吸引力的靶标，因为它控制着许多 细菌感染的主要机制，包括产生毒素，粘合剂，免疫 逃避和生物膜形成。这些过程可能会对人类产生宽度和毁灭性的影响 健康。许多病原细菌都利用QS在宿主身上发动同步攻击 达到了高细胞密度，从而压倒了宿主的防御机制。合成分子 能够阻止QS代表抑制细菌病毒的直接方法。对这种QS抑制剂的兴趣 （QSI）在过去的20年中探索了（QSIS），但QSIS在体内活动的表征仍然 婴儿期。迄今为止的体内研究依赖于（i）QSI，其效力差，未知机制， 和/或脱靶效果； （ii）虽然易于执行的动物感染模型与 典型的皮肤伤口感染。需要新的化合物，方法和模型才能向前推动QS字段。 这个R21项目将利用PI最近开发的QSI（最可能的QSI）到 推进新方法和材料，以阻止金黄色葡萄球菌伤口感染。这些目标将是 通过追求两个目标完成：（1）调查QSI减弱金黄色葡萄球菌的能力 经过良好测试的皮肤伤口感染的小鼠模型的感染，以及（2）表征 QSI具有当前抗生素的QSI，以探索交织物并增强伤口感染中的细菌清除率。两个都 目标将使用可降解的聚合物整合持续的释放策略来探索和定义最佳 在伤口中使用QSI的输送方法。我们的调查将由一个> 15的专家团队领导 多年的集体协作经验，并将PI的合成QSI与Co-IS的专业知识结合在一起 基于材料的药物输送方法，临床微生物学和伤口感染的动物模型。 该项目的结果将大大扩展对动物模型中细菌QS的理解 为人类伤口感染，并为QS抑制作用作为改善疾病的途径提供了批判性验证。