Project Grant R01AI175635

NOVEL ANTIFUNGAL AGENTS AGAINST COCCIDIOIDOMYCOSIS - PROJECT SUMMARY. FUNGAL INFECTIONS CAUSED BY DIMORPHIC FUNGI COCCIDIOIDES IMMITIS AND COCCIDIOIDES POSADASII ARE ENDEMIC TO THE SOUTHWESTERN PARTS OF THE UNITED STATES AND THE SELECTED AREAS IN THE WESTERN HEMISPHERE. WHILE MOST INFECTIONS ARE MILD AND, SYMPTOMATIC PNEUMONIA CAN BE EXTREMELY DIFFICULT TO TREAT AND REQUIRES LIFELONG AZOLE THERAPY UNDERSCORING THE NEED FOR NEW THERAPEUTIC OPTIONS. IN THIS RESPECT, TARGETING THE HIGH-OSMOLARITY GLYCEROL (HOG) MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) PATHWAY, AND, SPECIFICALLY, HYBRID HISTIDINE KINASES (HHKS), REPRESENTS A PROMISING APPROACH BECAUSE HHKS ARE NOT PRESENT IN HUMANS BUT ARE CRITICAL COMPONENTS OF CELLULAR RESPONSES TO OXIDATIVE STRESS IN PATHOGENIC FUNGI. WE HAVE IDENTIFIED A NATURAL PRODUCT CANDIDATE THAT SHOWS POTENT FUNGICIDAL ACTIVITY AGAINST COCCIDIOIDES IN A MURINE MODEL. THE OVERARCHING GOAL OF THIS COLLABORATIVE PROJECT IS TO OPTIMIZE ANTIFUNGAL ACTIVITY OF SYNTHETIC ANALOGS AS A POTENTIAL LEAD FOR VALLEY FEVER TREATMENT. IN AIM 1, WE WILL PERFORM RATIONAL SAR STUDY ON A LEAD CANDIDATE BY INTRODUCING MODIFICATIONS IN THREE DISTINCT PARTS OF THE MOLECULE. IN AIM 2, WE WILL STUDY THE MECHANISM OF ACTION OF THE LEAD CANDIDATES AND FINE-TUNE IN SILICO MODEL TO GUIDE RATIONAL ANALOG PREPARATION. IN AIM 3, WE WILL PERFORM PK/PD STUDIES AND VALIDATE THE ACTIVITY OF THE OPTIMIZED CANDIDATE IN A MURINE MODEL OF COCCIDIOIDOMYCOSIS. COLLECTIVELY, THIS STUDY WILL RESULT IN A SMALL MOLECULE FUNGICIDE WITH OPTIMIZED PROPERTIES FOR FUTURE PRE-CLINICAL WORK.