This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).
INTELLECTUAL MERIT: The long-term goal of this project is to develop new, broad-spectrum antimicrobial agents. The central hypothesis is that the preassembly of membrane-active polymer chains will enhance their cooperative ability to perforate the membrane, leading to an increase in antimicrobial potency as compared to single linear polymer chains. The study will focus on the creation of star- and bundle-shaped polymers that contain multiple polymer chains assembled onto a core molecule, thus presetting the geometrical features for each class of polymers. By utilizing complex macromolecular frameworks, the PI seeks to understand how these three-dimensional scaffolds can influence function in interactions with cell membranes, and to use this knowledge in the further rational design of synthetic biomaterials for clinical and medicinal uses. Additionally, the use of these architectures provides a unique opportunity to not only specifically tune the display of polymer arms to create optimal lytic agents, but also to provide novel insight into the mechanism of action of membrane-active compounds more broadly. As the general mechanism of antimicrobial peptides and polymers remains highly controversial, in part because the lack of suitable tools presents a formidable experimental roadblock, this work will significantly advance the field. Similarly, these studies will be invaluable in providing a detailed understanding of polymer-membrane interactions, improving our ability to rationally design and engineer further iterations of polymeric antimicrobial agents.
BROADER IMPACTS: The interdisciplinary nature of the proposed research will provide an important educational opportunity for the students and postdoctoral fellows in the PI?s and the PI?s collaborators? labs. The students will explore a broad range of relevant literature in journal clubs that will cement their theoretical understanding of their efforts in the laboratory. The PI is also dedicated to improving the knowledge of students outside of his direct supervision; in line with the PI?s current research, the topics of antibiotic resistance and toxicity of materials will be incorporated into the Biomaterials course that the PI teaches in the University of Michigan School of Dentistry. Looking even more globally, the PI has initiated several international research collaborations with research groups at Nagoya University in Japan. These interactions will allow students not only to gain scientific knowledge directly from world experts, but also to obtain valuable insight into the scientific practices, particularly for those students who are able to take part in our new international student exchange program. Finally, the PI is committed to providing these and similarly engaging research opportunities for a variety of students, and looks forward to his continued participation in the University of Michigan programs for undergraduate and underrepresented students.
