Drug Delivery with Fewer Fouls: Localized Antibiotic Release and Reduced Surface Biofouling with Glutathione-conjugated Hydrogels

Abstract

Systemic antibiotics are the standard of care for acute bacterial skin and skin structure infections (ABSSSI), but low drug perfusion at the site of infection and higher rates of antibiotic resistance necessitates the development of novel approaches to increase antibiotic concentrations at target sites. Wound dressings provide a more direct and convenient approach to antibiotic delivery for ABSSSI. However, wound dressings are limited due to being available as pre-loaded devices with fixed antibiotic concentrations. To begin to address this limitation, we have recently demonstrated the use of glutathioneconjugated poly(ethylene glycol) [GSH-PEG] hydrogels for the loading and release of charge-bearing therapeutic molecules.Herein, we evaluate the antibacterial and antibiofilm activities of rationally selected therapeutics released from GSH-PEG hydrogels against a panel of Gram-positive and Gram-negative bacterial isolates. In parallel, we assess the safety of the GSH-PEG hydrogels and their released therapeutic molecules on human dermal fibroblasts (hDFAs). GSH-PEG hydrogels passively loaded with meropenem or vancomycin successfully released the antibiotics and inhibited the growth of Pseudomonas aeruginosa and Staphylococcus aureus, respectively. Furthermore, these hydrogels effectively reduced biofilm formation in biofilm-producing strains of these bacteria. Antibiotics released from GSH-PEG hydrogels did not significantly influence hDFAs proliferation and migration, suggesting an absence of toxicity. In addition to controlling the delivery of antibiotic drugs, we examined the influence of GSH-conjugation on the fouling of protein and bacteria to the polymeric dressing material. Dressing materials with excessive fouling of proteins and bacteria may hamper wound closure and/or promote biofilm formation. Following incubation in an aqueous medium, albumin adsorption was significantly lower in GSHconjugated as compared to unconjugated hydrogel. GSH-conjugated hydrogels also demonstrated markedly lower bacterial adsorption as compared to unconjugated hydrogels and cotton gauze, a traditional wound dressing. The zwitterionic GSH ligands within hydrogels permit selective therapeutic delivery while reducing biofouling, highlighting the GSH-PEG hydrogel platform as a promising candidate for use as a wound dressing material.