Tandem Drug Delivery From Hydrogels for Inhibition of Antibiotic Resistance Emergence

Tandem Drug Delivery from Hydrogels for Inhibition of Antibiotic Resistance Emergence

Andrew L. Vasilakes*, David A. Puleo**, J. Zach Hilt*, Thomas D. Dziubla*.

 *Department of Chemical and Materials Engineering, University of Kentucky.

**Center for Biomedical Engineering, University of Kentucky.

 

Abstract: Due to the emergence of antibiotic resistant strains of bacteria, the medical community is facing a major challenge with a decreasing number of useful antibiotics available worldwide. In order to counter this disturbing trend, new strategies must be developed to actively inhibit bacterial antibiotic resistance emergence in wounds. One such approach is the co-delivery of antibiotics with agents that directly inhibit evolutionary adaptive mechanisms, e.g., reactive oxygen species (ROS) mediated antibiotic resistance emergence. It has been shown that the endogenous production of hydrogen peroxide can result in increased bacterial resistance by signaling an increase DNA break/repair malfunctioning, leading to genetic heterogeneity In this work, a biodegradable hydrogel with a small molecule antibiotic, vancomycin, and large molecule antioxidant payload, catalase, was developed to achieve sustained co-release with the intention of interfering with the ability of Staphylococcus aureus to develop antibiotic resistance under sub-lethal antibiotic insult. The antibiotic and antioxidant co-loaded poly(β-amino ester) (PβAE) hydrogels exhibit catalase release for 17 days via ¹²⁵I radiolabeling, and displayed catalase activity after PβAE polymerization in 10 mM hydrogen peroxide with an ODP/HRP assay. Vancomycin release proceeded for 7 days under PBS sink conditions. This release correlated with an antibacterial zone of inhibition against S. aureus for 9 days as measured using a modified Kirby-Bauer assay. Importantly, catalase was still active after hydrogel synthesis, and the presence of catalase showed no modification to release characteristics of vancomycin or activity. Extended release of both antibiotic and antioxidant over a targeted period was achieved. Using the newly developed PβAE hydrogel, future testing will determine the efficacy of reducing antibiotic resistance emergence.