This project investigates how antimicrobial molecules and inhaled antibiotics are inactivated by anionic polyelectrolytes in mucus, and thereby contribute to persistent airway infections. In cystic fibrosis (CF), such infections take an extreme form and are the primary cause of death. Using recent fundamental advances in bioengineering and biophysics, this multi-disciplinary work aims to design and test new antimicrobials and therapeutic strategies to enhance human airway defense.
Using a combination of state-of-the-art synchrotron x-ray diffraction and computer simulations, this research will isolate and characterize the structure and stability of electrostatic complexes of endogenous antibacterial proteins and anionic polyelectrolyte components in infected mucus. This is an application of recent ideas developed in soft matter physics on electrostatic interactions in aqueous media. These structural tendencies will be examined in model systems and in sputum collected from cystic fibrosis (CF) patients. Using this combined knowledge, prototypical charge-reduced "non-stick" versions of antimicrobial proteins will be designed for the electrostatic environment of the CF airway. In a complementary approach, biocompatible unbinding agents designed to dissolve electrostatic complexes between antimicrobials and anionic polymers in the airway will be rationally designed and tested.
Broader impacts of the project are: - An understanding of the new rules governing these combinations of fundamental interactions will have a transformative impact in soft matter physics and colloid science. - Water purification will be an emerging crisis both in the U.S. and internationally in the next 30 years. By adding multivalent salts to contaminated water, macromolecular impurities are condensed into aggregates that are removed through sedimentation. Despite widespread use, these processes are not well understood. The methods developed in this proposal for engineering electrostatic interactions will be directly relevant for rational design of condensing agents for water purification. - In the previous NSF support, members of the present research team has helped coach a Science Olympiad team from Campus Middle School for Girls in Urbana, as well as mentored a high school student who went on to represent the US in the International Science Fair, by involving her in research. These efforts will be continued. - The multi-disciplinary nature of the proposed work will provide ample educational opportunities for the new kind of hybrid scientists necessary in this emerging field. Moreover, when appropriate, results from this work have been incorporated into the PI's advanced undergraduate/graduate classes.
