ABSTRACT We propose a treatment to overcome infection by methicillin-resistant Staphylococcus aureus (MRSA) via a new mechanism of action: “quorum sensing inhibition”. MRSA is the most prevalent opportunistic pathogen implicated in burn wounds and once a sufficient number of bacteria colonize a wound (i.e., a “quorum”), they communicate via the Accessory Gene Regulator (Agr) pathway to upregulate virulence factor production and invasion via cell- cell signaling. Halting this communication (i.e., quorum sensing inhibition) is a powerful means of hamstringing MRSA virulence, and thereby augmenting host immune response, that does not rely on traditional antibiotics. w- Hydroxyemodin is a new natural product (fungal secondary metabolite) that we have recently demonstrated provides robust quorum sensing inhibition when administered topically. To deliver w-hydroxyemodin topically, we propose to use a novel, sprayable hydrogel-based burn wound dressing: the HydrAid Wound Dressing. This dressing is sprayed-on easily and quickly, gelling in situ to form a soft, elastic and mechanically robust hydrogel dressing significantly faster than commercial hydrogel sheets (or other Advanced Dressings) can be applied (especially over complex surfaces, e.g., hands, feet, elbows). To change the dressing, a dissolution solution is applied that dissolves the gel within minutes thereby alleviating or averting altogether the mechanical peeling and unintentional debridement that cause intractable pain and trauma for patients and caregivers alike. Thus, the w-hydroxyemodin-loaded HydrAid dressing overcomes the dual challenges of bacterial infection and patient pain common to the majority of 2nd degree burn wounds. Importantly, this combination product is intended as an adjuvant to current antibiotic regimens. While future clinical success may warrant investigation as a monother- apy, until such time, due to the polymicrobial nature of wound infections and the fact that not all pathogens utilize the Agr pathway, combination with traditional antibiotics will be a clinical necessity. As part of an ongoing Phase II SBIR (R44 GM125412) we have already established large-scale production of HydrAid dressing material com- ponents, demonstrated utility (of the unloaded version) in vivo and are manufacturing prototypes and evaluating pain metrics in a large-animal burn model. For the present application, in which w-hydroxyemodin is loaded in the HydrAid dressing, we have demonstrated the ability to load and release therapeutically relevant levels of w- hydroxyemodin and to combat MRSA infections in vivo in mice by augmenting the immune system and reducing MRSA virulence. This project addresses three key inflection points on the critical path for further development of this technology, including: Aim 1: Optimize the w-hydroxyemodin-loaded HydrAid wound dressing formulation to provide sustained release of therapeutic concentrations of w-hydroxyemodin for three days. Aim 2: Determine th...