Host Targeted Therapy for Drug Resistant Salmonella and Francisella infection

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Abstract The formation of antibacterial drug resistance is a public health crisis and has led to increaseing healthcare costs and even death. Drug resistance can occur when an antibiotic directly kills a pathogen or prevents its growth because of selective pressure. This phenomena has generated various multi-drug resistant bacterial species that are a global public health concern. Most antibacterial therapeutics target the pathogen in an attempt to clear infection. However, more recently the concept of antibacterial therapeutics that target host specific pathways has been developed. These pathways can potentially prevent infection, virulence, replication, and proliferation. Therapies that target these pathways could potentially treat traditional antibiotic resistant strains. Additionally, targeting the host instead of the pathogen could prevent the development of drug resistance because the therapy could activate pathways that fight resistance and activate the host’s defense mechanisms. Futhermore, because many pathogens take advantage of similar pathways, there is a potential for developing therapies that target a broad-spectrum of pathogens. We were one of the first groups to use a host-targeted therapeutic (HTT) for the treatment of a pathogen that is considered a Threat Level of Serious by the CDC. This HTT does not work directly on intracellular pathogens but instead targets host cell promoting pathways that result in clearance of the pathogen. Additionally, this HTT has broad-spectrum activity against pathogens including a NIAID Category A class pathogen. We have both in vitro and in vivo data showing activity and increase in survival. In order to increase activity we have encapsulated this compound in a novel biomaterial that is acid sensitive. This acid sensitivity allows for the intracellular release of encapsulated cargo. Our preliminary data shows that encapsulation of the HTT drastically enhances the efficacy of the compound compared to non-encapsulated form. In this proposal, we propose on performing medicinial chemistry on our HTT to develop a compound with increased activity. We will formulate this compound in our novel polymeric particles for both in vitro and in vivo testing. We will perform various biological assays to determine activity of optimized compounds. In order to do this, our proposal is a partnership between the University of North Carolina, National Taiwan University, and the Research Triangle Institute (RTI). This partnership will be invaluable in obtaining an optimized HTT compound that has activity against a broad spectrum of pathogens as it incoporates academic researchers in the field and RTI’s experience with drug development.