High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections

• DOI: 10.1073/pnas.0609370104
• Publication Date: 2007-03-06T01:44:34Z
• Authors: Lixin Zhang; Kezhi Yan; Yu Zhang; Ren Huang; Jiang Bian; Chuansen Zheng; Haixiang Sun; Zhihui Chen; Nuo Sun; Rong An; Fangui Min; Weibo Zhao; Ying Zhuo; Jianlan You; Yongjie Song; Zhenyan Yu; Zhiheng Liu; Keqian Yang; Hong Gao; Huanqin Dai; Xiaoli Zhang; Jian Wang; Chengzhang Fu; Gang Pei; Jintao Liu; Si Zhang; Michael Goodfellow; Yuanying Jiang; Jun Kuai; Guochun Zhou; Xiaoping Chen
• Keywords: 0303 health sciences; Antifungal Agents; Drug Evaluation, Preclinical; Microbial Sensitivity Tests; Cell Line; 3. Good health; Disease Models, Animal; Drug Combinations; Immunocompromised Host; Mice; 03 medical and health sciences; Ketoconazole; Mycoses; Drug Resistance, Fungal; Depsipeptides; Animals; Humans; Algorithms

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 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. Seven of them showed little cytotoxicity against human hepatoma cells. Fractionation of the active extracts revealed beauvericin (BEA) as the most potent component, because it dramatically synergized KTC activity against diverse fungal pathogens by a checkerboard assay. Significantly, in our immunocompromised mouse model, combinations of BEA (0.5 mg/kg) and KTC (0.5 mg/kg) prolonged survival of the host infected with Candida parapsilosis and reduced fungal colony counts in animal organs including kidneys, lungs, and brains. Such an effect was not achieved even with the high dose of 50 mg/kg KTC. These data support synergism between BEA and KTC and thereby a prospective strategy for antifungal therapy.