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.