| Description |
Invasive fungal infections contribute to 1.6 million deaths annually. Many of these fungi can cause disease in immunocompetent individuals; however, most infections occur in the immunocompromised, leaving the patient with a clear disadvantage. Treatment options available are few, with limited drug targets and high costs. These treatments also display host toxicity and can take long periods of time, allowing for resistance to emerge against this limited antifungal arsenal. These challenges often result in exceedingly high mortality rates for invasive fungal infections. In order to enhance therapy options, this study focused on the disease cryptococcosis and the widely available and cost-effective antifungal fluconazole. Cryptococcosis causes 220,000 cases and 180,000 deaths annually. In resource-limited areas, patients are often treated with fluconazole alone which can result in mortality rates as high as 80%. To improve fluconazole therapy and treat cryptococcosis and potentially other fungal infections, we investigated synergistic drug interactions, as these would result in increased inhibition of the etiological agent of the disease Cryptococcus neoformans. Though these interactions are often rare (4-10%), our method correctly identified important interactions with fluconazole 46% of the time. We identified 40 molecules that synergize and 19 molecules that antagonize (decreased inhibition in combination) with fluconazole. Of these interactions, we identified an antagonistic interaction with a common antibacterial, nafcillin sodium, as well as an experimental synergistic molecule, berbamine iv hydrochloride. Furthermore, we identified a promising synergistic anticholinergic, dicyclomine hydrochloride, which increases the permeability of cryptococcal fungal cells and the mislocalization of fungal transporters and is relevant in an in vivo model of cryptococcosis. |
