CAREER: Lipo-cyclic antimicrobial peptidomimetics that disrupt bacterial membranes

细菌感染对抗生素治疗的耐药性是21世纪最大的公共卫生问题之一。天然抗微生物化合物能够破坏细菌膜，因此代表了一种有前途的新方法来规避抗微生物药物耐药性。然而，这些化合物稳定性低，活性适中。作为一类新的抗菌化合物，脂环γ - a肽一直在研究者的实验室中进行开发。它们的设计是为了模仿天然材料，但避免了它们的缺点。该提案旨在优化这类新型抗生素的有效性，并弄清楚它们的确切工作原理。这种追求将使研究生和本科生获得有机合成，化学生物学和微生物学的跨学科训练。脂环γ - a肽的设计、制备和研究将导致一类新的抗生素的产生，从而避免抗生素耐药性。此外，该项目将整合教学、研究和推广活动，以扩大坦帕社区当地青年对科学和研究的接触。有了这个奖项，化学学部的生命过程化学项目资助了南佛罗里达大学的蔡剑锋博士，以探索类似天然抗菌肽（AMPs）的新型脂环类肽的基本化学、结构-功能关系和作用机制。基于初步的研究结果和最初的抗菌肽模拟物的设计假设，研究团队将：(1)设计和合成先前制备的抗菌γ - a肽的新型脂环类似物。(2)通过结构-功能关系（SFR）研究，确定对一组重要的革兰氏阳性和革兰氏阴性细菌具有有效和广谱活性的先导化合物。(3)研究脂环γ - a肽及其衍生物是否会破坏细菌膜。该项目涉及的方法包括设计和合成新的多肽模拟物，评估其抗菌活性和选择性，利用荧光和电子显微镜研究细菌膜完整性，以及膜去极化。

The resistance of bacterial infections to antibiotic treatment is one of the biggest public health concerns in the 21st century. Natural antimicrobial compounds are capable of disrupting bacterial membranes, and therefore represent a promising new approach to circumvent antimicrobial resistance. Nevertheless, these compounds suffer from low stability and moderate activity. Lipo-cyclic gamma-AApeptides have been under development in the investigator's laboratory as a new class of antimicrobial compounds. They were designed to mimic the natural materials, but to avoid their drawbacks. The proposal aims to optimize the effectiveness of this new class of antibiotics, and to figure out exactly how they work. This pursuit will allow graduate and undergraduate students to acquire interdisciplinary training in organic synthesis, chemical biology and microbiology. The design, preparation and study of lipo-cyclic gamma-AApeptides will lead to a new class of antibiotics that can avoid antimicrobial resistance. Moreover, this project will integrate teaching, research and outreach activities to broaden exposure to science and research for the local youth population in the Tampa community.With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Jianfeng Cai from the University of South Florida to explore the fundamental chemistry, structure-function-relationship and mechanism of action of novel lipo-cyclic peptidomimetics that act like natural antimicrobial peptides (AMPs). Building upon preliminary results and the original hypothesis for the design of antimicrobial peptidomimetics, the research team will: (1) Design and synthesize novel lipo-cyclic analogues of previously prepared antimicrobial gamma-AApeptides. (2) Through structure-function-relationship (SFR) studies, identify lead compounds that display potent and broad-spectrum activity against a panel of significant Gram-positive and Gram-negative bacteria. (3) Investigate if bacterial membrane disruption is the general bactericidal mechanism of lipo-cyclic gamma-AApeptides and their derivatives. The methods involved in the project include design and synthesis of new peptide mimics, evaluation of their antimicrobial activity and selectivity, and the study of bacteria membrane integrity using fluorescence and electron microscopy, and membrane depolarization.