The full range of antibiotic-resistant microbes found in hospitals and the broader environment represent a "clear and present danger" to the general public, first responders, and military personnel. Effective response to this public health challenge necessitates adoption of an "outside-the-box" strategy for the de novo design of novel classes of microbicides. The goal of this NSF Career award is to develop a novel self-assembling antimicrobial nanofiber (SAAN) platform for safer and more effective therapeutic administration of antimicrobial peptides (AMPs) compared to conventional treatment options. Systematic engineering of SAANs has minimized host cell cytotoxicity, improved their protease-resistance and their antimicrobial activity against broad-spectrum bacteria. The success of the proposed work will open new avenues for AMP-based antimicrobial therapy to treat a variety of infectious diseases found in both civilian hospitals and military facilities. The fundamental knowledge developed from the proposed research activities will provide a powerful new glossary of fundamental design principles for the synthesis and deployment of AMPs. It will have a transformative impact on the multi-billion-dollar research focused on conventional antibiotics and AMPs by re-engineering and "re-formatting" thousands of available AMPs in the peptide databank to form SAANs, thereby greatly boosting their therapeutic potential. The multidisciplinary research involving chemistry, microbiology, engineering, nanoscience, and pharmaceutical sciences provides ample opportunities to train and educate students at all levels. The fundamental biomaterials design, supramolecular chemistry and antimicrobial delivery principle will be integrated into various research and educational activities, particularly through summer research opportunities provided to high school students to promote their scientific research interests and enhance their career awareness. Educational partnership with local high school will be established to provide summer research internship to high school teachers to incorporate the fundamental knowledge of the proposed research into various high school curriculum.
Technical section:
The discovery of antimicrobial peptides (AMPs) has brought tremendous opportunities to overcome the prevalence of bacterial resistance to commonly used antibiotics due to their direct action against bacterial membrane. However, despite AMPs' exceptional bactericidal activity in vitro, their susceptibility to proteases, limited circulation half-lives and severe host cell toxicity represent critical hurdles to their widespread use. This CAREER award supported by the Biomaterials program in the Division of Materials Research to Clarkson University focuses on a new paradigm of Self-Assembled Antimicrobial Nanofibers (SAANs) as a vehicle-free AMP delivery system to alleviate the drawback associated with conventional AMPs. In SAANs, AMPs serve as both therapeutics and key structural components to program and direct the assembly through highly specific intermolecular interactions. Through the proposed work, we will build a toolbox of cationic de novo designed peptides with expanded chemical functionality by which to construct various SAANs families, and explore the effect of new functional groups on the molecular and supramolecular packing of SAANs, antimicrobial activity and hemocompatibility. Fundamental knowledge about the structure-activity relationship is essential for the design of new antimicrobial nanomaterials with precise control over molecular structure, nanostructure, stimuli-responsive antimicrobial activity and exquisite biocompatibility. The impact of this proposal lies in that SAANs could potentially be established as a new and unique AMP delivery platform with well-defined filamentous structure and the ease of incorporating multi-therapeutics for combinatorial antimicrobial and chemotherapy to treat various human diseases. The proposed project will integrate supramolecular chemistry, biomaterials design and antimicrobial delivery principles and techniques with various education and outreach activities for students at all levels.
