Antimicrobial Polymers for Treatment of Multidrug-Resistant Wound Biofilm Infections

About This Grant

Project Summary/Abstract Antimicrobial Polymers for Treatment of Multidrug-Resistant Wound Biofilm Infections The goal of the proposed research is to create a new polymer therapeutic for multidrug resistant (MDR) biofilm infections. The refractory nature of biofilm infections makes them non-responsive to standard antibiotics, a situation exacerbated by acquired antibacterial resistance. In our research, we have integrated the nanomedicine capabilities of Rotello with the wound biofilm expertise of Patel to develop poly(oxanorborneneimide) antimicrobial polymers (PONI-AMPs) These polymers kill biofilm-based bacteria with minimal effects on host cells. PONI-AMP therapeutics had good efficacy (killing ≥99% of bacteria in biofilms) in an in vivo wound biofilm model developed by Patel. In our proposed research, Rotello will 'evolve' PONI-AMP therapeutics using amino acid sidechains as an initial source of molecular diversity. These polymers will be modeled by Van Lehn using atomistic simulations to generate descriptors that will be used in conjunction with biological properties (antimicrobial efficacy and mammalian cell toxicity) to provide an integrated synthetic, computational, and machine-learning feedback strategy for designing new polymers. The polymers will then be incorporated into a hydrogel to provide controlled release of PONI-AMP to treat wound infections. PONI-AMPs in hydrogel will be tested in vitro and in vivo using realistic and challenging wound biofilm models. Aim 1. Maximize antibacterial and antibiofilm activity through polymer evolution. Rotello will synthesize polymers featuring diverse sidechain functionality and screen for antibacterial and antibiofilm activity against multiple MDR pathogens, with testing of mammalian cell viability performed to determine therapeutic selectivity. Van Lehn will integrate computational chemistry with machine learning to develop descriptors that will be used to evolve polymers to maximize antimicrobial efficacy and minimize mammalian toxicity. Broad-spectrum activity will be targeted, including methicillin-resistant Staphylococcus aureus (MRSA). Rotello will screen evolved PONI-AMPs against MRSA and other pathogens, and Patel will perform testing in multi-pathogen models. Aim 2. Wound hydrogels for nanoparticle delivery. Rotello will develop hydrogel materials (PONI-AMP-hydrogel) for wound covering and PONI-AMP delivery that will provide intimate and sustained contact with wounds and controlled delivery of polymers to biofilms in wound beds. Rotello will screen for efficacy using bioluminescent MRSA biofilms, and Patel will determine efficacy against multi-pathogen biofilms. Aim 3. In vivo and ex vivo testing of PONI-AMP-hydrogel antimicrobials. Patel and Rotello will perform in vivo murine studies of PONI-AMP-hydrogel treatments using collaboratively developed bioluminescent MRSA biofilm wound models, focusing on bactericidal activity, wound healing, and purulence reduction. Patel will perform multi-pathogen murine studies and ex vivo studies using multi-pathogen infected porcine dermal explants.