(71i) 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.