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

项目摘要 这个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 材料和探索创新的方法，以防止皮肤伤口的细菌感染。皮肤 伤口感染导致超过600万患者的痛苦和痛苦， 美国每年250亿美元。目前可用于治疗这些感染的药物几乎 由于细菌耐药性的上升而完全耗尽。从根本上说，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， 提供应对这一威胁的手段，并对医疗保健产生重大影响。目前的建议旨在 通过靶向化学信号通路--群体感应（QS）--来开发这样一种方法， 在许多皮肤伤口常见的抗生素耐药细菌中，包括金黄色葡萄球菌， 细菌中的QS已经成为抗毒力领域中有吸引力的靶点，因为它控制了许多 细菌感染的主要机制，包括毒素产生、粘附、免疫 逃避和生物膜形成。这些过程会对人类产生广泛的破坏性影响。 健康许多病原菌只有在宿主感染QS后才利用QS对其发动同步攻击。 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代表了抑制细菌毒力的直接途径。对此类QS抑制剂的兴趣 在过去的20年里，QSIs（QSIs）已经爆炸，但是QSIs在体内的活性的表征仍然存在于其研究中。 婴儿期。迄今为止的体内研究依赖于（i）效力差、机制未知的QSI， 和/或脱靶效应;或（ii）动物感染模型，虽然易于实施，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（最有效的QSI）， 推进新的方法和材料，以阻止S。金黄色葡萄球菌伤口感染这些目标将 通过追求两个目标来实现：（1）调查QSI衰减S的能力。金黄色 感染，和（2）表征皮肤伤口感染的良好测试的小鼠模型中的组合。 QSI与当前抗生素一起探索协同作用并增强伤口感染中的细菌清除。两 AIMS将使用可降解聚合物整合持续释放策略，以探索和定义最佳的 在伤口中使用QSI的递送方法。我们的调查将由一个专家小组领导， 多年的集体合作经验，并将PI的合成QSI与Co-Is的专业知识结合起来， 基于材料的药物递送方法、临床微生物学和伤口感染的动物模型。的 该项目的结果将显着扩大在动物模型相关的细菌QS的理解 并为QS抑制作为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.