Strategies to Block Skin Wound Infection by Intercepting Bacterial Cell-to-Cell Signaling

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PROJECT SUMMARY This R21 project will use potent chemical inhibitors of bacterial cell-to-cell signaling to develop new materials and explore innovative approaches to prevent bacterial infections in skin wounds. Skin wound infections cause suffering and distress in over 6 million patients and incur treatment costs totaling over $25 billion annually in the US. The current arsenal of drugs available to treat these infections is now almost completely depleted due to the rise of bacterial resistance. Fundamentally new ‘anti-virulence’ approaches that move beyond conventional antibiotic strategies and target bacterial virulence rather than cell growth could provide means to address this threat and have major impacts on medical care. This current proposal seeks to develop such an approach by targeting a chemical signaling pathway—quorum sensing (QS)—that controls virulence in many of the antibiotic resistant bacteria common to skin wounds, including Staphylococcus aureus. QS in bacteria has emerged as an attractive target in the anti-virulence field because it controls many of the primary mechanisms that underlie bacterial infection, including toxin production, adhesion, immune evasion, and biofilm formation. These processes can have widespread and devastating effects on human health. Many pathogenic bacteria utilize QS to launch synchronized attacks on their hosts only after they have achieved a high cell density, thereby overwhelming the host’s defense mechanisms. Synthetic molecules capable of blocking QS represent a direct approach to inhibit bacterial virulence. Interest in such QS inhibitors (QSIs) has exploded over the past 20 years, but characterization of the activities of QSIs in vivo remains in its infancy. The in vivo studies to date have relied on either (i) QSIs with poor potency, unknown mechanisms, and/or off-target effects; or (ii) animal infection models that, while easy to perform, are not highly relevant to typical skin wound infection. New compounds, methods, and models are required to push the QS field forward. This R21 project will leverage a QSI recently developed by the PI—the most potent QSI to be reported—to advance new approaches and materials to block S. aureus wound infections. These objectives will be accomplished by the pursuit of two Aims: (1) investigation of the ability of the QSI to attenuate S. aureus infections in a well-tested mouse model of skin wound infection, and (2) characterization of combinations of the QSI with current antibiotics to explore synergies and enhance bacterial clearance in wound infections. Both Aims will integrate sustained release strategies using degradable polymers to explore and define optimal delivery approaches for the use of QSIs in wounds. Our investigations will be led by an expert team with >15 years of collective collaborative experience and unite the PI’s synthetic QSIs with the expertise of the Co-Is in materials-based drug delivery approaches, clinical microbiology, and animal models of wound infection. The outcomes of this project will significantly expand the understanding of bacterial QS in an animal model relevant to human wound infection and provide critical validation for QS inhibition as a route to ameliorate disease.