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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该 R21 项目将使用细菌细胞间信号传导的有效化学抑制剂来开发新的材料并探索预防皮肤伤口细菌感染的创新方法。伤口感染给超过 600 万患者带来痛苦和困扰，并产生总计超过 100 万美元的治疗费用美国目前用于治疗这些感染的药物每年已接近 250 亿美元。由于细菌耐药性的增加而完全耗尽。超越传统的抗生素策略并针对细菌毒力而不是细胞生长当前的提案旨在提供应对这一威胁并对医疗保健产生重大影响的方法。通过针对控制化学信号通路——群体感应（QS）——开发这样的方法皮肤伤口常见的许多抗生素耐药细菌的毒力，包括金黄色葡萄球菌。细菌中的 QS 已成为抗毒力领域的一个有吸引力的目标，因为它控制着许多细菌感染的主要机制，包括毒素产生、粘附、免疫这些过程可能对人类产生广泛的破坏性影响。许多病原菌只有在感染后才利用QS对其宿主发起同步攻击。达到高细胞密度，从而压倒宿主的防御机制。能够阻断 QS 代表了抑制细菌毒力的直接方法。 QSI（QSI）在过去 20 年中呈爆炸式增长，但 QSI 体内活性的表征仍然处于其发展阶段。迄今为止的体内研究依赖于（i）效力较差、机制未知的 QSI，和/或脱靶效应；或（ii）动物感染模型，虽然易于执行，但与典型的皮肤伤口感染需要新的化合物、方法和模型来推动 QS 领域的发展。该 R21 项目将利用 PI 最近开发的 QSI（报告中最有效的 QSI）来这些目标将是阻止高级金黄色葡萄球菌伤口感染的新方法和材料。通过追求两个目标来实现：(1) 研究 QSI 减弱金黄色葡萄球菌的能力在经过充分测试的皮肤伤口感染小鼠模型中进行感染，以及（2）组合的表征 QSI 与现有抗生素探索协同作用并增强伤口感染的细菌清除率。目标将使用可降解聚合物整合缓释策略，以探索和定义最佳我们的调查将由超过 15 人的专家团队领导。多年的集体协作经验，并将 PI 的综合 QSI 与 Co-Is 的专业知识结合起来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。该项目的成果将显着扩大对相关动物模型中细菌 QS 的理解人类伤口感染，并为 QS 抑制作为改善疾病的途径提供关键验证。