Mechano-microbiology: how physical forces control bacterial-host interactions

 描述（由申请人提供）：人类健康在很大程度上取决于我们与细菌的相互作用。与细菌病原体相关的危险自1800年以来一直受到重视。但我们正在输掉与这些“坏”细菌的战争，因为细菌对已知抗生素的耐药性进化速度远远快于我们开发新抗生素的速度。在这里，我建议通过开发一种新的抗生素策略来解决这一危机，该策略利用了我们发现的机械敏感性毒力调节因子，这些调节因子独立于生长来控制发病机制。所有现有的抗生素要么杀死细菌，要么抑制它们的生长。的 因此，我们用来治疗病原性感染的每一种工具都给了抗药性突变体一个巨大的适应性优势。因此，靶向机械敏感性毒力调节可以减轻抗性的上升，代表“抗性抗性”治疗策略。我们最近发现了一种机械传感器PilY 1，它的破坏消除了铜绿假单胞菌的毒力而不影响生长，使我们能够直接测试这个有希望的假设。 与此同时，随着我们控制致病细菌的能力越来越弱，最近的研究表明，我们不能再简单地将细菌视为我们的敌人。事实上，许多“健康”的人体生理机能，从胃肠道功能到糖尿病，再到免疫系统的发育，都取决于人体与其“好”细菌伙伴之间的共生关系。然而，我们仍然非常不善于操纵我们的微生物群。在这里，我提出了一种（据我所知）完全新颖的方法来操纵细菌种群，利用我的实验室最近发现的细菌具有“触觉”，它们用于感知和响应机械环境，以及我在工程分析方面的专业知识，以研究细菌-宿主在模拟人体内细菌遇到的力学环境中的相互作用。 具体来说，我建议定量分析体内的机械力

 DESCRIPTION (provided by applicant): Human health is in large part dictated by our interactions with bacteria. The dangers associated with bacterial pathogens have been appreciated since the 1800's. But we are losing the war against these "bad" bacteria because bacteria are evolving resistance to known antibiotics far faster than we are developing new antibiotics. Here I propose to address this crisis by developing a new antibiotic strategy that leverages our discovery of mechanosensitive virulence regulators that control pathogenesis independently of growth. All existing antibiotics either kill bacteria or inhibit their growth. The very tool we use to treat pathogenic infections thus gives antibiotic-resistant mutants a huge fitness advantage. Consequently, targeting mechanosensitive virulence regulation could mitigate the rise of resistance, representing a "resistance-resistant" therapeutic strategy. Our recent identification of a mechanosensor, PilY1, whose disruption eliminates P. aeruginosa virulence without affecting growth, enables us to directly test this promising hypothesis. At the same time as we are growing less capable of controlling pathogenic bacteria, recent studies show that we can no longer simply view bacteria as our foes. Indeed much of "healthy" human physiology, from gastrointestinal function to diabetes to immune development depends on the symbiotic relationship between the human body and its "good" bacterial partners. However, we remain woefully bad at manipulating our microbiome. Here I propose a (to my knowledge) completely novel approach to manipulating bacterial populations that leverages my lab's recent discovery that bacteria have a "sense of touch" that they use to sense and respond to their mechanical environment and my expertise in engineering assays to study bacterial- host interactions in environments that mimic the mechanics encountered by bacteria within humans. Specifically, I propose to quantitatively assay how mechanical forces in the body