A Combination Therapy Approach to Treating Drug Resistant Fungal Infections

DESCRIPTION provided by applicant Despite the introduction of newer triazoles and echinocandins invasive fungal infections IFIandapos s including invasive candidiasis IC remain very difficult to treat with currently available antifungals The annual cost burden of treating nosocomial fungal infections exceeds $ billion a year in the United States alone Worldwide the annual incidence of IC is about Children suffering from the most common pediatric cancer acute leukocytic leukemia have an approximate mortality rate however if the patient develops invasive candidiasis their mortality rate increases to times to Currently only three classes of antifungal drugs are employed to treat IC and no new class has been introduced to the market for thirteen years It has been widely recognized that antifungal treatments which address mechanisms of drug resistance and could be combined with existing therapeutics would provide a tremendous advantage over currently available treatments Unfortunately unlike cancer chemotherapy there are relatively few treatment regimens that productively combine different antifungals to achieve better therapeutic outcomes and address drug resistance without the added burden of drug toxicity Work performed in the lab of our colleague Prof Joe Heitman and others has revealed the tremendous therapeutic potential of inhibiting the fungal protein calcineurin Calcineurin inhibition compromises the cell wall stress response of Candida albicans NCACandapos s Aspergillus fumigatus Cryptococcus neoformans and other pathogenic fungi Furthermore when combined with triazoles echinocandins or allylamines calcineurin inhibitors are highly synergistic and can reduce the MIC value by a factor of or more It has also been observed that resistant clinical isolates of C albicans A fumigatus and other fungi become susceptible to antifungal therapeutics when combined with a calcineurin inhibitor both in vitro and in vivo However the lack of a potent antifungal calcineuin inhibitor that does not cause immunosuppression has hindered progress in exploiting this novel target Moreover calcineurin inhibitors are typically are large structurally complex andgt Daltons molecules and this has hindered the facile creation of analogues for testing Employing newly developed chemistry and structural insight we propose developing a potent non immunosuppressive fungal calcineurin inhibitor building on progress from our Phase I project Aim Generate closely related analogs of hits resulting from screens from Phase I Aim Characterize compounds in vitro for advancement Iterate library as required Aim Characterize compounds in vivo for pharmacokinetics and efficacy PUBLIC HEALTH RELEVANCE Fungal infections represent a significant challenge due to the limited armamentarium available to treat diseases caused by fungi Nosocomial infections caused by Candida albicans have a andgt mortality rate Amplyx proposes a new combination therapy approach to treating drug resistant fungal infections via the design and synthesis of non immunosuppressive molecules to inhibit fungal calcineurin that can be co administered with existing antifungals