Targeting the host response to limit infection by intracellular bacterial pathogens

Antibiotic development has traditionally focused on drugs that target the pathogen but resistance inevitably developsAn attractive alternative is to develop drugs that target the host response and in particular for facultative obligate intracellular bacterial pathogenswhich rely on the host for disease progressionIntracellular bacterial pathogens manipulate the host cytoskeletal system to their advantage during various stages in infectionIn particular a number of medically important pathogens activate the MEK ERK cascadewhich is known to be important in cytoskeletal dynamicsFDA approved inhibitors of MEK are available but their efficacy is limited by their toxicityWe discovered and developed a specific small molecule inhibitor for RSKa downstream effector of the MEK ERK signaling pathwayIn preliminary experimentsusing Yersinia pseudotuberculosis as a model intracellular bacterial systemwe identified that RSKinhibition reduced the number of viable bacteria in infected macrophageswhich correlated with inhibition of Ypseudotuberculosis induced cytoskeletal rearrangementFurthermorebacterial infection can result in sepsiswhich results in a loss of epithelial integrityImportantlywe identified that RSKregulates a gene signature enriched in immune response signaling in epithelial cellssuggesting that a RSKinhibitor will dampen the epithelial generated immune response and therebyprotect epithelial integrityIn support of these data inhibiting MEK signaling pathway was found to decrease organ dysfunctionFor the phase I programBlue Ridge BiosciencesLLCa reagent discovery and development companyin collaboration with Vanderbilt University Medical Centerwill assess the feasibility of targeting RSKas a drug target for facultative obligate intracellular bacterial pathogens that activate the MEK ERK pathwayFrancisella tularenis will be used as proof of principleThe Specific Aims aredetermine whether RSKlimits propagation of Ftularenis in primary macrophages in vitrodetermine whether inhibition of RSKprotects the integrity and viability of lung epithelial cells in vitroandtest whether inhibition of RSKusing a RSKknockout mouse model will ameliorate infection by Ftularenis in vivoData generated in this proposal will be analyzed using the appropriate statistics for end point and longitudinal analysisThese data will be used to support a phase II for the continued development of a RSKinhibitor as a novel strategy for combating infection NarrativeAntibiotic resistance is a major global health problemThis proposal will provide preliminary data to support the development of a novel therapeutic strategy that targets the host response to infection by intracellular bacterial pathogensTargeting the host response to infection will dramatically reduce the incidence of resistance