Theory Assisted Design, Synthesis and Biological Activity of Bacteria-Targeting Nanostructures

Project Summary/Abstract The goal of this project is to develop nanostructures that are selective for bacteria and to create a theoretical framework (in silico model) that can be used to predict the activity of nanostructures and their behavior and interactions with bacteria. Bacterial infections are a serious health problem that affects the human population. Further, the emergence of resistant bacterial strains has made the problem even more serious. Two pathogens of particular concern are Staphylococcus aureus and Acinetobacter baumannii. These pathogens are a main cause of nosocomial skin and lung infections and are prevalent in immunocompromised patients and hospital settings. To deal with these serious pathogens we propose to create nanostructures with intrinsic antibacterial activity that can also target the bacteria by including siderophore molecules. In addition, we propose to develop theoretical (computer) models that can be used to understand the biological action of the nanostructures and can be used to design new nanostructures. To develop these systems, we have devised four specific aims. Specific Aim 1. Computer-Guided Design of PA nanostructures. We will design several PA molecules and use theoretical tools to select the PAs to be prepared. We will prepare nanostructures and test their antimicrobial activity and cell toxicity. Specific Aim 2. Developing Bacteria Targeting Nanostructures. We will modify the best PA molecules with siderophores. We will prepare nanostructures and test them against diverse bacteria. We will also use the data to refine our MOLT system Specific Aim 3. Membrane Interactions and in Vivo Activity. We will study the ability of nanostructures to disrupt membranes. We will also study the role of the siderophores. Finally, we will evaluate their antibacterial activity using a Wax moth larvae in vivo model. Specific Aim 4. Developing a Multi-Resolution Model model. We will combine the statistical mechanics and molecular dynamic simulations to predict and understand the shape of the nanostructures, their activity. We will also study the interactions of the PA nanostructures with membranes using both models. We will then combine the models to get a better picture of the membrane disruption process. We will use the model to develop Quantitative Structure-Activity Relationships that can be used to make better nanostructures.