High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections
Open accessAbstract
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.
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Beauvericin was found to be well tolerated by human cells and to potentiate azole efficacy against Candida parapsilosis in a systemic infection model.
“it was found to be well tolerated by human cells and to potentiate azole efficacy against Candida parapsilosis in a systemic infection model by a mechanism that remains enigmatic12.”
From Dual action antifungal small molecule modulates multidrug efflux and TOR signaling (2016) · cites this paper as [12]
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- Authors
- 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.
- Affiliations
- Chinese Academy of Sciences (CN)
- Guangdong Laboratory Animals Monitoring Institute (CN)
- *Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, China;
- Newcastle University (GB)
- Second Military Medical University (CN)
- Wyeth Research, Cambridge, MA 02140
- Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Beijing 510663, China;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-03-13
- Volume
- 104
- Issue
- 11
- Pages
- 4606-4611
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1838648
- OpenAlex
- W1965575582
- Cited by
- 248
- References
- 44
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 10 · 2023: 9 · 2022: 12 · 2021: 16 · 2020: 19 · 2019: 11 · 2018: 10 · 2017: 12 · 2016: 23 · 2015: 14 · 2014: 19 · 2013: 19 · 2012: 19
- FWCI
- 7.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Teesside University Research Portal (Teesside University) (publishedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Mycotoxins in Agriculture and Food
- Keywords
- microbial natural products, beauvericin, ketoconazole, antifungal synergy, fungal infection, Candida parapsilosis, immunocompromised patients, combination antifungal therapy, microbial metabolites, cytotoxicity
- MeSH terms
- Algorithms, Animals, Antifungal Agents, Cell Line, Disease Models, Animal, Drug Combinations, Drug Evaluation, Preclinical, Humans, Ketoconazole, Microbial Sensitivity Tests, Mycoses, Immunocompromised Host, Drug Resistance, Fungal, Depsipeptides, Mice
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