Research Project
9621963
PROJECT SUMMARY Staphylococcus aureus bacteremia (SAB) is one of the most common blood stream infections and has mortality rates of 20% or higher. The pathogenicity of SAB is due to various virulence factors which facilitate microbial colonization of the host and contribute to immune evasion. These virulence factors elicit a host response 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 which can lead to death in SAB patients. Navigen?s objective is to reduce morbidity and mortality associated with SAB infections by modifying this host response. Specifically, we propose to advance development of a small-molecule ARF6 inhibitor to reduce vascular leak elicited by the infection while having no adverse effect on immunity-based clearance of the pathogen. Navigen has discovered a first-in-class chemical series of direct, small-molecule ARF6 inhibitors that show robust efficacy in a wide variety of conditions characterized by excessive vascular leak, including mouse models of lipopolysaccharide (LPS)-induced acute lung injury (ALI), Acinetobacter baumannii (AB) pneumonia, Candida albicans systemic infection, Plasmodium berghei ANKA-induced severe cerebral malaria, and cecal ligation and puncture (CLP)-induced polymicrobial sepsis. These ARF6 inhibitors were discovered using a high-throughput biochemical, fluorometric nucleotide exchange assay to screen 100,000 compounds from a commercially available compound library. Medicinal chemistry optimization efforts have resulted in synthesis and evaluation of over 200 analogs. We have selected NAV-5188 as our lead compound and propose to develop this ARF6 inhibitor as an adjunctive therapy for treatment of SAB.
