[R01] A high throughput screen to identify broad-spectrum, mold-active antifungals
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2031-06-30
Importo max: 582.699 EUR
Paese: US
Descrizione
PROJECT SUMMARY
Invasive mold infections (IMIs) are a major cause of morbidity and mortality among susceptible
populations worldwide. Risk factors for IMIs include immunomodulatory therapies such as chemotherapy, long-
term corticosteroid use, viral infections, and diabetic ketoacidosis. IMIs are caused by a handful of
environmental molds, but the most common are Aspergillus fumigatus and Zygomycetes, including Mucor and
Rhizopus spp. Currently, there are three classes of antifungals used to treat IMIs; however, despite available
treatments, mortality rates are typically ~50% but reach 80-100% for some mold species and patient cohorts. A
major challenge in treating IMIs is lack of efficacy of current antifungals against molds due to intrinsic and
acquired resistance of mold species to clinical antifungals.
To address the need for mold-active antifungals, we developed and validated a resazurin-based
screening assay to screen directly with the Zygomycete Mucor circinelloides, representing the first high
throughput screen against a non-Aspergillus mold. In Aim 1A, we will utilize this assay to screen 150,000 drug
like molecules. Our primary hits will be prioritized in Aim 1B to identify those with broad spectrum activity and
acceptable in vitro mammalian toxicity. Next, in Aim 1C, we will test the bioavailability of each compound with
murine pharmacokinetic studies to identify the best candidates for in vivo use.
In Aim 2, we will narrow our focus to one scaffold that will be subject to mechanism-driven SAR
studies. We will utilize several approaches to define the mode and mechanism of action including chemical
genomics, phenotyping and generation of resistant mutants. Iterative rounds of chemical optimization and
compound testing will enable identification of potent antifungal molecules with limited toxicity. Finally, in Aim 3,
the top compounds from our optimized series will be tested in murine models of fungal disease including
disseminated mucormycosis. The completion of this award will result in a novel, mold-active compound for
IND-enabling studies for the treatment of life-threatening IMIs.
Istituzione: UNIVERSITY OF IOWA
PI: Sarah R. Beattie
Progetto: 1R01AI201844-01
Settori: National Institute of Allergy and Infectious Diseases
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