Development of a novel broad spectrum antifungal therapeutic targeting glycosylphosphatidylinositol (GPI) biosynthesis and cell wall biogenesis - widespread azole resistance among candida and…

Development of a novel broad spectrum antifungal therapeutic targeting glycosylphosphatidylinositol (GPI) biosynthesis and cell wall biogenesis - widespread azole resistance among candida and aspergillus SPP. Along with emerging echinocandin resistance in C. Glabrata and C. Auris raises the specter of untreatable multidrug resistant fungal infections, even as advances in medicine (cancer chemotherapy, organ transplant, premature infants, HIV/aids therapy) have increased the size of the vulnerable population. Our proposal aims to develop a novel broad spectrum antifungal therapeutic targeting glycosylphosphatidylinositol (GPI) biosynthesis to treat life threatening infections due to drug resistant candida and aspergillus with no cross resistance to existing agents. Our aims are: aim 1 (phase 1). Demonstrate improved efficacy is achievable by optimizing pharmacokinetic (PK) properties of the series. Perform metabolic identification (METID) studies on M743, M720, and the hydrolyzed core lacking the sidechain to identify oxidative metabolic hotspots to guide a limited lead optimization (lead OPT) effort to improve PK properties of the series while maintaining potency, spectrum, target selectivity, and minimizing cytotoxicity. Test up to 2 new analogs in a murine systemic infection model of candidiasis with and without 1-aminobenzotriazole (ABT) PK enhancer codosing. Milestone 1. Based on METID studies, synthesize up to 30 new M743 analogs. An analog showing an IP-administered dose-dependent > 3 LOG10 reduction in fungal burden in a murine candidiasis model (i.e. superior to M720 efficacy) with or without ABT codosing will identify the key (and addressable) liability of the series and warrant advancement of the program to PH 2. Aim 2 (phase 2). M743 scale up, lead OPT and in vitro characterization of compounds. Produce M743 on scale sufficient to supply a full lead OPT effort based on METID data and emerging SAR. Characterize analogs as in aim 1 with additional emphasis on PK, MOA, reduced serum binding, and cytotoxicity. Milestone 2. Obtain 3G of M743; semisynthesize up to 100 new analogs. Identify up to 3 analogs with acceptable potency and PK (without ABT codosing), along with validated target engagement, for 3 log reduction in burden over therapeutic duration) and overall favorable drug-like properties will be selected as a preclinical candidate.