Mechanical Regulation of Ultra-Sensitivity in E. Coli Flagellar Motors

大肠杆菌鞭毛马达超灵敏的机械调节

• 批准号: 9398711
• 负责人: Pushkar Prakash Lele
• 金额: $ 25.52万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9398711
• 关键词: Antibiotic Resistance; Bacteria; Binding; Biological; Catheters; Cells; Cessation of life; Chemotaxis; Clinical; Data; Development; Devices; Escherichia coli; Exhibits; Filament; Foundations; Goals; Healthcare Systems; Hospitals; Infection prevention; Knowledge; Liquid substance; Mechanics; Mediating; Mission; Molecular; Molecular Conformation; Motor; Public Health; Regulation; Research; Resistance to infection; Role; Rotation; Signal Transduction; Solid; Stimulus; Surface; Switching Complex; Testing; Theoretical model; Therapeutic; Time; United States National Institutes of Health; Urinary tract infection; Work; acquired drug resistance; base; cell motility; combat; design; expectation; experimental study; extracellular; innovation; mechanical force; mechanotransduction; mutant; novel; prevent; response

PROJECT ABSTRACT Swarming motility, exhibited by many motile species of bacteria, has been implicated in the rapid invasion of hosts during urinary tract infections (UTIs). Annually, UTIs result in several thousand deaths in the US alone and represent a significant load on the public healthcare system. Swarming motility is substrate-associated and is driven by bacterial flagellar motors that rotate extracellular, helical filaments to generate thrust on the cell- body. Although chemotaxis is not required for swarming, the functioning of a molecular switch that enables reversals in the direction of motor-rotation is indispensable. The switch is activated by CheY-P, an intracellular response-regulator that is regulated by the chemotaxis network. Upon CheY-P-binding, cooperative interactions within the multi-subunit switch-complex drive concerted transitions from counterclockwise (CCW) to clockwise (CW) conformations with increasing likelihood, resulting in changes in the direction of rotation. Our recent results indicate that flagellar motors sense mechanical forces, arising from contact with solid substrates, and that leads to the inhibition of switching. In a short time the motor adapts to these forces and recovers the ability to reverse directions. However, the molecular underpinnings responsible for adaptation remain unclear. Thus, there is a critical need to determine how the switch adapts to mechanical stimuli to promote swarming. Without such knowledge, the potential to capitalize on antivirulence strategies as therapeutic approaches to combat swarming-mediated host-invasion and antibiotic resistance will likely remain limited. Our long-term goal is to contribute toward the development of new clinically useful antivirulence strategies that target bacterial swarming and colonization. Our overall objective in this application is to determine the molecular mechanisms whereby the switch adapts perfectly to mechanical signals and promotes swarming. Our central hypothesis is that motor-mechanosensing (sensing of mechanical signals) results in the tuning of ultra-sensitivity through the modulation of allosteric and cooperative interactions within the switch. The rationale for the proposed work is that a determination of the mechanism of mechanical control of ultra-sensitivity is likely to provide a conceptual framework for the development of strategies to interfere with switch adaptation, and to mitigate swarming. At the completion of the proposed research, it is our expectation to have quantitatively explained the mechanisms underlying switch-adaptation and modulation of ultra-sensitivity by mechanical forces. Results are expected to have an important positive impact because a detailed understanding of switching near substrates will provide a strong foundation for novel substrate-design in biomedical devices, including catheters, which will target the motor-switch to inhibit swarming.

项目摘要