ARF6 Inhibitor as Adjunctive Therapy for Treatment of SA Bacteremia

PROJECT SUMMARYStaphylococcus aureus bacteremiaSABis one of the most common blood stream infections and has mortality rates ofor higherThe pathogenicity of SAB is due to various virulence factors which facilitate microbial colonization of the host and contribute to immune evasionThese virulence factors elicit a host response that can include a severe systemic inflammatory reactioncytokine stormand ensuing vascular leakVascular leak is a fundamental element in the pathogenesis of circulatory shock and multiple organ failure which can lead to death in SAB patientsNavigen s objective is to reduce morbidity and mortality associated with SAB infections by modifying this host responseSpecificallywe propose to advance development of a small molecule ARFinhibitor to reduce vascular leak elicited by the infection while having no adverse effect on immunity based clearance of the pathogenNavigen has discovered a first in class chemical series of directsmall molecule ARFinhibitors that show robust efficacy in a wide variety of conditions characterized by excessive vascular leakincluding mouse models of lipopolysaccharideLPSinduced acute lung injuryALIAcinetobacter baumanniiABpneumoniaCandida albicans systemic infectionPlasmodium berghei ANKA induced severe cerebral malariaand cecal ligation and punctureCLPinduced polymicrobial sepsisThese ARFinhibitors were discovered using a high throughput biochemicalfluorometric nucleotide exchange assay to screencompounds from a commercially available compound libraryMedicinal chemistry optimization efforts have resulted in synthesis and evaluation of overanalogsWe have selected NAVas our lead compound and propose to develop this ARFinhibitor as an adjunctive therapy for treatment of SAB PROJECT NARRATIVE Staphylococcus aureus bacteremiaSABis one of the most common blood stream infections and has mortality rates ofor higherVascular leak is a fundamental element in the pathogenesis of circulatory shock and multiple organ failure which can lead to death in SAB patientsWe propose to advance development of a smallmolecule ARFinhibitor to reduce vascular leak elicited by the infection while having no adverse effect on immunity based clearance of the pathogen