Interdisciplinary Initiatives Program Round 11 - 2022
Project Investigators:
Eric Appel, Materials Science & Engineering
Lynette Cegelski, Chemistry
Abstract:
Antimicrobial resistance is a massive and growing threat to human health around the world. Recent forecasts indicate that without the development of novel antimicrobial therapies, premature deaths caused by antibiotic-resistant pathogens could exceed ten million annually in 2050, overtaking cancer-related deaths. Unfortunately, little progress has been made in recent years in the development of new classes of antibiotics, and antibiotic-resistant strains of bacteria continue to arise worldwide at an alarming rate. The mechanisms for antimicrobial resistance are molecularly defined and include inhibition of drug uptake, modification of the drug target, inactivation of the drug, and enhanced drug efflux. While several new broad-spectrum antibiotics operating by a membrane disruption mechanism have been reported that are both highly effective and unlikely to lead to the development of resistant strains, their translation has been hampered by either complex synthesis, poor scalability, toxicity by hemolytic activity, or poor stability.
To address this unmet clinical need, we will develop a novel class of inexpensive and stable broad-spectrum polyacrylamide-derived copolymer antibiotics by leveraging a combination of rational chemical design and high-throughput synthesis and screening approaches. As a class of materials, polyacrylamides are inexpensive to synthesize at scale and demonstrate remarkable chemical stability, facilitating global access without need for cold chain storage and distribution. Moreover, the large number of commercially available monomers make this class of perfectly well-suited to high-throughput combinatorial copolymer synthesis approaches for evaluation of a large chemical space. In the proposed work, we will generate a large library of hundreds of distinct copolymers and will evaluate how physicochemical factors such as molecular weight, hydrophobicity, charge identity, and charge density affect the ability of these polymers to kill bacteria by a membrane permeabilization mechanism without exhibiting hemolytic activity using highly parallelized in vitro assays. Finally, we will explore the in vivo efficacy of top candidate copolymers in a mouse model of pneumonia. This project will bring together trainees with disparate backgrounds to collaborate on the development of novel broadspectrum antibiotic copolymers that are inexpensive, scalable, highly stable, immune to antibiotic resistance, and non-toxic to mammals due to their selective mechanism of action to address a critical global need for novel antibiotics.
