A unique strategy for reshaping the antibiotics model: chemokine-inspired therapeutics for targeting the host and pathogen to counter infections caused by multidrug-resistant bacteria

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PROJECT SUMMARY Background: Antibiotics have traditionally been developed and deployed as stand-alone antimicrobials, comprising a single destructive pressure to kill microorganisms. While initially successful, this model presents minimal barrier against the emergence of resistance. Thus, the arms race between man and microbe has reached a perilous tipping point: many clinically-significant bacterial pathogens are increasingly resistant to multiple, and in some cases all, available antibiotics. For nearly 15 years the Hughes laboratory and colleagues have investigated the antimicrobial actions of the human chemokine CXCL10. This multifunctional effector mediates receptor-dependent host-targeted activities, including immune defense and regenerative processes, as well as direct bactericidal effects against multidrug-resistant (MDR) bacterial pathogens. Towards harnessing the therapeutic utility of these actions, our collaborative team has divided the principal biological activities of CXCL10 into a pair of individually-tailored derivatives: peptide P1 exerts host-targeted effects, while peptide D8 kills diverse MDR bacteria. We hypothesize that this exciting breakthrough provides a tunable arrangement from which to balance and apply a 'multi-fold' therapeutic strategy that directly kills invading bacteria, enlists immune defense to combat infection, and promotes host recovery. Approach: To test this innovative concept, we propose to deploy CXCL10-derived peptides to counter wound/surgical site infections, the most common and costly type of healthcare-associated infection. Using an established murine model amenable to measuring wound healing and infection outcomes, we will: [Aim 1] distinguish peptide P1 dose/dosage strategies for affecting host-immune engagement and the promotion of tissue repair/regeneration; and [Aim 2] determine the therapeutic efficacy of bactericidal peptide D8, unaided and together with peptide P1, against wound infections caused by carbapenem-resistant Enterobacteriaceae (CRE) and methicillin-resistant Staphylococcus aureus (MRSA), clinically-challenging etiologic agents of wound infections in humans. Animal research will be enriched by in vitro studies that elaborate physiologic and bactericidal modes-of-action, measure peptide biostability, assess potential lead-peptide cytotoxicity, and evaluate the emergence of peptide D8-resistant bacterial phenotypes. The proposed research will be accomplished by a cross-disciplinary group of collaborators with demonstrated expertise in the areas of clinical infectious diseases, regenerative medicine, immunotherapy, peptide chemistry, and therapeutics development. Outcomes: The proposed research activities are expected to yield entirely new anti-infective and regenerative technologies, and establish a unique paradigm whereby antimicrobial therapies not only kill pathogens, but also conscript host processes to combat infection, diversify selective pressures, and promote recovery. The original resources and compelling preliminary data described in this application attest to the feasibility and likelihood of successfully achieving these outcomes towards addressing the mounting burden of MDR bacteria.