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

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 & 11 others Xiaoli Zhang, Jian Wang, Chengzhang Fu, Gang Pei, Jintao Liu, Si Zhang, Michael Goodfellow, Yuanying Jiang, Jun Kuai, Guochun Zhou, Xiaoping Chen

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 approximately 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.

Original languageEnglish
Pages (from-to)4606-11
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number11
DOIs
Publication statusPublished - 13 Mar 2007

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Ketoconazole
Mycoses
Biological Products
Microbial Colony Count
Animal Structures
Immunocompromised Host
Candida
Hepatocellular Carcinoma
Kidney
Lung
Survival
Mortality
Brain
Therapeutics
beauvericin

Cite this

Zhang, Lixin ; Yan, Kezhi ; Zhang, Yu ; Huang, Ren ; Bian, Jiang ; Zheng, Chuansen ; Sun, Haixiang ; Chen, Zhihui ; Sun, Nuo ; An, Rong ; Min, Fangui ; Zhao, Weibo ; Zhuo, Ying ; You, Jianlan ; Song, Yongjie ; Yu, Zhenyan ; Liu, Zhiheng ; Yang, Keqian ; Gao, Hong ; Dai, Huanqin ; Zhang, Xiaoli ; Wang, Jian ; Fu, Chengzhang ; Pei, Gang ; Liu, Jintao ; Zhang, Si ; Goodfellow, Michael ; Jiang, Yuanying ; Kuai, Jun ; Zhou, Guochun ; Chen, Xiaoping. / High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 11. pp. 4606-11.
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abstract = "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 approximately 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.",
author = "Lixin Zhang and Kezhi Yan and Yu Zhang and Ren Huang and Jiang Bian and Chuansen Zheng and Haixiang Sun and Zhihui Chen and Nuo Sun and Rong An and Fangui Min and Weibo Zhao and Ying Zhuo and Jianlan You and Yongjie Song and Zhenyan Yu and Zhiheng Liu and Keqian Yang and Hong Gao and Huanqin Dai and Xiaoli Zhang and Jian Wang and Chengzhang Fu and Gang Pei and Jintao Liu and Si Zhang and Michael Goodfellow and Yuanying Jiang and Jun Kuai and Guochun Zhou and Xiaoping Chen",
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Zhang, L, Yan, K, Zhang, Y, Huang, R, Bian, J, Zheng, C, Sun, H, Chen, Z, Sun, N, An, R, Min, F, Zhao, W, Zhuo, Y, You, J, Song, Y, Yu, Z, Liu, Z, Yang, K, Gao, H, Dai, H, Zhang, X, Wang, J, Fu, C, Pei, G, Liu, J, Zhang, S, Goodfellow, M, Jiang, Y, Kuai, J, Zhou, G & Chen, X 2007, 'High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 11, pp. 4606-11. https://doi.org/10.1073/pnas.0609370104

High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections. / Zhang, Lixin; Yan, Kezhi; Zhang, Yu; Huang, Ren; Bian, Jiang; Zheng, Chuansen; Sun, Haixiang; Chen, Zhihui; Sun, Nuo; An, Rong; Min, Fangui; Zhao, Weibo; Zhuo, Ying; You, Jianlan; Song, Yongjie; Yu, Zhenyan; Liu, Zhiheng; Yang, Keqian; Gao, Hong; Dai, Huanqin; Zhang, Xiaoli; Wang, Jian; Fu, Chengzhang; Pei, Gang; Liu, Jintao; Zhang, Si; Goodfellow, Michael; Jiang, Yuanying; Kuai, Jun; Zhou, Guochun; Chen, Xiaoping.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 11, 13.03.2007, p. 4606-11.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections

AU - Zhang, Lixin

AU - Yan, Kezhi

AU - Zhang, Yu

AU - Huang, Ren

AU - Bian, Jiang

AU - Zheng, Chuansen

AU - Sun, Haixiang

AU - Chen, Zhihui

AU - Sun, Nuo

AU - An, Rong

AU - Min, Fangui

AU - Zhao, Weibo

AU - Zhuo, Ying

AU - You, Jianlan

AU - Song, Yongjie

AU - Yu, Zhenyan

AU - Liu, Zhiheng

AU - Yang, Keqian

AU - Gao, Hong

AU - Dai, Huanqin

AU - Zhang, Xiaoli

AU - Wang, Jian

AU - Fu, Chengzhang

AU - Pei, Gang

AU - Liu, Jintao

AU - Zhang, Si

AU - Goodfellow, Michael

AU - Jiang, Yuanying

AU - Kuai, Jun

AU - Zhou, Guochun

AU - Chen, Xiaoping

PY - 2007/3/13

Y1 - 2007/3/13

N2 - 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 approximately 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.

AB - 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 approximately 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.

U2 - 10.1073/pnas.0609370104

DO - 10.1073/pnas.0609370104

M3 - Article

VL - 104

SP - 4606

EP - 4611

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 11

ER -