Antimicrobial-Membrane Interactions in Living Bacteria

在化学系生命过程化学(CLP)项目的支持下，天普大学的戴海龙教授正在研究细菌膜如何调节它们与周围环境的相互作用，特别是那些含有抗菌剂的细菌。该项目的目标是提供基础知识，为未来开发更有效的抗菌剂提供潜力，这些抗菌剂可以摧毁致病细菌并降低细菌对抗生素的耐药性。将通过定量检测小分子的反应来研究小分子和合成蛋白质在改变细菌细胞膜通透性方面的作用，这些小分子与光的相互作用使其在与细胞膜成分结合时能够非常敏感地进行检测。这种强大的基于光的方法将被用来测试如何在膜与附近的化学物质相互作用时在膜上形成微孔，或者通过改变分子在细菌膜上的通道中移动的方式来测试。戴教授将把高中、大学和博士生纳入研究计划，为高度多样化的学生群体提供非常广泛的科学技能，以帮助他们追求自己的职业目标。进一步扩大该项目影响的是为费城市中心中学生举办的夏令营。总而言之，该项目将通过培训和让年轻人参与研究来帮助加强科学队伍，这些研究旨在为有关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。抗菌素耐药性细菌感染的问题日益严重，这证明了该研究领域的重要性。据世界卫生组织和联合国预测，到2050年，这些感染每年将导致1000万人死亡。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发挥调节功能。我们将使用非线性光学光谱学和显微技术来描述各种膜传输机制。这些将包括基于输入通道、外排泵和脂质双层通透性的那些，它们在调节对细菌生存至关重要的分子的细胞内浓度和保护细菌免受有害化合物或过度丰富的原本被认为是有用的化合物的影响方面发挥着关键作用。这项研究将从根本上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，并减少膜的保护功能。实验将旨在收集对了解膜如何履行其对活细胞的调节功能至关重要的数据，以及设计开发更有效的抗菌剂的策略。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.