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

项目总结 这个R21项目将使用细菌细胞间信号传递的有效化学抑制剂来开发新的 材料，并探索防止皮肤伤口细菌感染的创新方法。皮肤 伤口感染给600多万名患者带来痛苦和痛苦，治疗费用总计超过 在美国每年250亿美元。目前可用于治疗这些感染的药物现在几乎是 由于细菌耐药性的上升，完全耗尽了。从根本上说是一种新的“抗毒力”方法 超越传统的抗生素策略，针对细菌毒力而不是细胞生长可能 提供应对这一威胁的手段，并对医疗保健产生重大影响。这项目前的提案旨在 通过针对化学信号通路--群体感应(QS)--开发这样一种方法，它控制着 皮肤伤口常见的许多耐抗生素细菌中的毒力，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靶点，因为它控制着许多 细菌感染的主要机制，包括毒素产生、黏附、免疫 逃避和生物膜的形成。这些过程可能会对人类产生广泛而毁灭性的影响 健康。许多致病细菌只有在拥有了QS之后，才利用QS对宿主发动同步攻击 获得了高细胞密度，从而压倒了宿主的防御机制。合成分子 能够阻断QS代表了一种直接抑制细菌毒力的方法。对这类QS抑制剂的兴趣 (QSIS)在过去的20年里取得了爆炸性的进展，但对QSIS在体内的活动的表征仍在其 婴儿期。到目前为止，体内研究依赖于(I)效力不佳、机制未知的QSIS， 和/或非目标效应；或(Ii)动物感染模型，虽然很容易执行，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领域向前发展。 这个R21项目将利用PI最近开发的QSI-要报告的最强大的QSI-到 开发新的方法和材料来阻止金黄色葡萄球菌的伤口感染。这些目标将是 通过追求两个目标来完成：(1)调查QSI对金黄色葡萄球菌的减毒能力 在经过良好测试的皮肤伤口感染的小鼠模型中的感染，以及(2) QSI与目前的抗生素，以探索协同作用，并加强伤口感染的细菌清除。两者都有 AIMS将整合使用可降解聚合物的持续释放策略，以探索和定义最佳 创面使用QSIS的给药方法。我们的调查将由一个专家团队领导，由&gt；15 多年的集体协作经验，并将PI的合成QSIS与Co-IS的专业知识相结合 基于材料的给药方法、临床微生物学和伤口感染的动物模型。这个 该项目的成果将显著扩展对相关动物模型中细菌QS的理解 对人类伤口感染的影响，并为QS抑制作为一种改善疾病的途径提供关键验证。

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.