Polyacrylamide-Based Antimicrobial Copolymers to Replace or Rescue Antibiotics
Shoshana C. Williams, Madeline B. Chosy, Carolyn K. Jons, Changxin Dong, Alexander N. Prossnitz, Xinyu Liu, Hector Lopez Hernandez, Lynette Cegelski, Eric A. Appel
Abstract
Antibiotics save countless lives each year and have dramatically improved human health outcomes since their introduction in the 20th century. Unfortunately, bacteria are now developing resistance to antibiotics at an alarming rate, with many new strains of "superbugs" showing simultaneous resistance to multiple classes of antibiotics. To mitigate the global burden of antimicrobial resistance, we must develop new antibiotics that are broadly effective, safe, and highly stable to enable global access. In this manuscript, we report the development of polyacrylamide-based copolymers as a class of broad-spectrum antibiotics with efficacy against several critical pathogens. We demonstrate that these copolymer drugs are selective for bacteria over mammalian cells, indicating a favorable safety profile. We show that they kill bacteria through a membrane disruption mechanism, which allows them to overcome traditional mechanisms of antimicrobial resistance. Finally, we demonstrate their ability to rehabilitate an existing small-molecule antibiotic that is highly subject to resistance development by improving its potency and eliminating the development of resistance in a combination treatment. This work represents a significant step toward combating antimicrobial resistance.