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The high mortality rate of immunocompromised patients with fungal infections and the limited availability of highly efficacious and safe agents demand the development of new antifungal therapeutics.To rapidly discover such agents,we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products.Specifically,a marine microbial natural product library was screened for hits that synergize the effect of a low dosage of ketoconazole (KTC) that alone shows little detectable fungicidal activity.Through screening of 20,000 microbial extracts,12 hits were identified with broad spectrum antifungal activity.