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

 描述(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。自1800年S以来，人们就意识到了与细菌病原体相关的危险。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产生的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，该策略利用我们发现的机械敏感毒力调节器来控制病程独立于生长。所有现有的抗生素要么杀死细菌，要么抑制它们的生长。这个 我们用来治疗病原体感染的每一种工具都给了抗生素耐药突变体一个巨大的适应优势。因此，靶向机械敏感性毒力调节可以减轻耐药性的上升，代表了一种“耐药”的治疗策略。我们最近鉴定出一种机械传感器PilY1，它的破坏可以在不影响生长的情况下消除铜绿假单胞菌的毒力，使我们能够直接测试这一有希望的假说。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，从胃肠功能到糖尿病再到免疫发育，许多“健康”的人类生理都依赖于人体与其“好的”细菌伙伴之间的共生关系。然而，可悲的是，我们仍然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)操纵细菌种群的全新方法，该方法利用了我的实验室最近的发现，即细菌具有感知机械环境并对其做出反应的“触觉”，以及我在工程分析方面的专业知识，以研究细菌与宿主在模仿细菌在人类体内遇到的机制的环境中的相互作用。具体地说，我建议定量分析身体中的机械力

 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