Antimicrobial-Membrane Interactions in Living Bacteria

在天普大学化学系生命过程化学（CLP）项目的支持下，戴海龙教授正在研究细菌膜如何调节其与周围环境的相互作用，特别是那些含有抗菌药物的细菌膜。该项目的目标是提供基础知识，为未来开发更有效的抗菌素提供潜力，这些抗菌素可摧毁致病细菌并减少细菌对抗生素的耐药性。小分子和合成蛋白在改变细菌细胞膜渗透性中的作用将通过定量检查小分子的反应来研究，这些小分子与光的相互作用允许它们在与细胞膜成分结合时非常敏感地检测到。这种强大的基于光的方法将被用来测试当膜与附近的化学物质相互作用时，膜上是如何形成小孔的，或者通过改变分子在细菌膜上的通道中移动的方式。戴教授将把高中生、大学生和博士生纳入研究项目，为高度多样化的学生提供广泛的科学技能，帮助他们追求自己的职业目标。进一步扩大项目影响的是费城内城中学生的夏令营。总而言之，该项目将通过培训和让年轻人参与研究，帮助加强科学队伍，旨在为细菌膜化学的重要基本问题提供答案，最终目标是提供解决细菌感染和抗生素耐药性的关键信息。这一研究领域的重要性得到了日益严重的抗微生物药物耐药性细菌感染问题的证明，据世界卫生组织和联合国预测，到2050年，每年将有1 000万人死亡。在这项研究中，戴教授将研究细菌复杂的壁结构如何对抗菌剂等外部分子行使其调节功能。我们将描述，使用非线性光学光谱和显微镜方法，各种膜运输机制。这些将包括那些基于进口通道、外排泵和脂质双分子层渗透性的机制，它们在调节细胞内分子浓度方面发挥关键作用，这些分子对细菌的生存至关重要，并保护细菌免受有害化合物或过量的有害化合物的侵害，否则被认为是有用的化合物。该研究将提供基本的了解抗菌剂如何与细菌膜的各种成分相互作用，使其更具渗透性并降低膜的保护功能。实验的目的是收集关键数据，以了解膜如何发挥其对活细胞的调节功能，以及为开发更有效的抗菌剂设计策略。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professor Hai-Lung Dai of Temple University is studying how bacterial membranes regulate their interactions with the surrounding environment, in particular those containing antimicrobial agents. The goal of this project is to provide fundamental knowledge that holds potential for future development of more effective antimicrobials that destroy disease-causing bacteria and reduce bacterial resistance to antibiotics. The role of small molecules and synthetic proteins in changing the permeability of bacterial cell membranes will be studied by quantitatively examining the response of small molecules whose interaction with light allows for their very sensitive detection when bound to cell membrane components. This powerful light-based method will be used to test how tiny holes are formed in the membrane upon membrane interaction with nearby chemicals or by changing how molecules move through channels in the membrane of bacteria. Professor Dai will integrate high school, college, and PhD students into the research program, providing a highly diverse group of students a very broad scientific skill set to help them pursue their career goals. Further broadening the impact of the project is a summer camp for Philadelphia inner city middle school students. In sum, the project will help strengthen the scientific workforce by training and exposing young minds to research aimed at providing answers to important fundamental questions about the chemistry of bacterial membranes with the ultimate goal of providing information key to addressing bacterial infections and antibiotic resistance. The significance of the research area is evidenced by the growing problem of antimicrobial-resistant bacterial infections, which are predicted by the World Health Organization and the United Nations to result in the death of 10 million people annually by 2050. In this study, Professor Dai will examine how the complex wall structures of bacteria exercise their regulatory functions on external molecules like antimicrobials. We will delineate, using both nonlinear optical spectroscopy and microscopy approaches, a variety of membrane transport mechanisms. These will include those based on import channels, efflux pumps, and lipid bilayer permeability, which play key roles in regulating intracellular concentrations of molecules critical to bacteria viability and protecting the bacteria from harmful compounds or an over-abundance of what would otherwise be thought to be useful compounds. The research will provide fundamental understanding of how antimicrobials interact with the various components of bacterial membranes to make them more permeable and reduce the protective functions of the membrane. Experiments will be designed to gather data critical for understanding how membranes perform their regulatory functions for living cells, as well as for designing strategies for developing more effective antimicrobials.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.