PROJECT SUMMARY Staphylococcus aureus bacteremia (SAB) is one of the most common blood stream infections and hasmortality rates of 20% or higher. The pathogenicity of SAB is due to various virulence factors which facilitatemicrobial colonization of the host and contribute to immune evasion. These virulence factors elicit a hostresponse that can include a severe systemic inflammatory reaction (cytokine storm) and ensuing vascular leak.Vascular leak is a fundamental element in the pathogenesis of circulatory shock and multiple organ failure whichcan lead to death in SAB patients. Navigen?s objective is to reduce morbidity and mortality associated with SABinfections by modifying this host response. Specifically, we propose to advance development of a small-moleculeARF6 inhibitor to reduce vascular leak elicited by the infection while having no adverse effect on immunity-basedclearance of the pathogen. Navigen has discovered a first-in-class chemical series of direct, small-molecule ARF6 inhibitors that showrobust efficacy in a wide variety of conditions characterized by excessive vascular leak, including mouse modelsof lipopolysaccharide (LPS)-induced acute lung injury (ALI), Acinetobacter baumannii (AB) pneumonia, Candidaalbicans systemic infection, Plasmodium berghei ANKA-induced severe cerebral malaria, and cecal ligation andpuncture (CLP)-induced polymicrobial sepsis. These ARF6 inhibitors were discovered using a high-throughputbiochemical, fluorometric nucleotide exchange assay to screen 100,000 compounds from a commerciallyavailable compound library. Medicinal chemistry optimization efforts have resulted in synthesis and evaluationof over 200 analogs. We have selected NAV-5188 as our lead compound and propose to develop this ARF6inhibitor as an adjunctive therapy for treatment of SAB.