PROJECT SUMMARY/ABSTRACT Mucormycosis is a deadly invasive infection caused by several fungal organisms belonging to the subphylum Mucormycotina, order Mucorales. The major risk factors include uncontrolled diabetes mellitus that results in hyperglycemia and ketoacidosis (DKA), other forms of acidosis, treatment with corticosteroids, solid organ or bone marrow transplantation, neutropenia, trauma and burns (e.g., wounded soldiers in Iraq and Afghanistan), malignant haematological disorders and deferoxamine therapy in patients receiving haemodialysis. The infection is generally acquired by inhalation of spores that are ubiquitous in nature and cause either rhino- orbital (almost exclusively in DKA patients) or pulmonary (mainly in neutropenic leukemic patients) disease. The treatment options for Mucormycosis are limited. There are currently no vaccines and only two antifungal agents approved by the USA FDA to treat this disease. The first is Amphotericin B (AmB) which has serious adverse effects, including nephrotoxicity, and very limited clinical success. Isavuconazole was recently approved to treat mucormycosis but it is not superior to AmB treatment. In the absence of surgical removal of the infected focus (such as excision of the eye in patients with rhinocerebral mucormycosis), antifungal therapy alone is rarely curative. Even when surgical debridement is combined with high-dose antifungal therapy, the mortality associated with mucormycosis is >50%. In patients with prolonged neutropenia or disseminated disease, mortality is 90-100%. Furthermore, since there are no federal requirements to report fungal infections, the true prevalence of mucormycosis is likely to be much higher than currently reported. The unacceptably high mortality rate, limited options for therapy and the extreme morbidity of highly disfiguring surgical therapy make it imperative to look for alternative strategies to treat and prevent mucormycosis. Our recently published work suggests that Mucorales species engage host cell receptors in order to invade host tissue through the vascular endothelium and the pulmonary epithelium. In Aim 1, we will explore the therapeutic potential of blocking the interaction between Mucorales fungi and host cell receptors. Aim 2 will focus on identifying and characterizing fungal-encoded drug targets with the goal of validating additional targets for novel, desperately needed anti- fungal therapies. The ultimate goal of the work proposed here is to develop novel antifungal strategies to either kill the fungus or disrupt molecular interactions that are important for disease progression of pulmonary mucormycosis.