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Discovery of deguelin derivatives in combination with fluconazole against drug-resistant Candida albicans

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Abstract

Candida albicans, as the most prevalent opportunistic pathogenic fungus, has caused great difficulty in its clinical management. At the same time, azole resistance is emerging as their extensive usage in clinical practice. In this case, the adoption of combination therapy has become a promising therapeutic strategy. In this study, a series of deguelin (Deg) derivative were prepared and identified with in vitro antifungal activity against drug-resistant C. albicans combined with fluconazole (FLC). The combination of Deg derivative 17c and FLC exhibited the best activity, with a fractional inhibitory combination index (FICI) of 0.02. The sensitization effect of 17c + FLC was further validated by the temporal fungicidal curve analysis. In addition, 17c + FLC also demonstrated inhibitory effects on the mycelial transformation and biofilm formation of resistant C. albicans, and significantly reduced the expression of key genes related to the RAS1/cAMP/PKA cell-transduction pathway.

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Abbreviations

Deg:

deguelin

FLC:

fluconazole

FICI:

fractional inhibitory combination index

DMF:

dimethylformamide

DCM:

dichloromethane

Rt:

room temperature

TLC:

thin-layer chromatography

TMS:

tetramethylsilane

PE:

petroleum ether

HRMS:

high resolution mass spectrum

ESI:

electrospray ionization

ppm:

parts per million

NMR:

nuclear magnetic resonance

MIC:

minimum inhibitory concentration

SD:

standard deviation

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (82260694, 82260805, 82260682), Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform (2022YKZY001), Applied Basic Research Foundation of Yunnan Province (202301AW070003, 202201AT070297), State Key Laboratory for Conservation and Utilization of Bio-Resource in Yunnan (2021KF004), Yunnan Provincial Science and Technology Department-Applied Basic Research Joint Special Funds of Yunnan University of Chinese Medicine (202101AZ070001-037), Project of Innovative Research Team of Yunnan Province (202005AE160005), Yun Ling Scholar Project to W-LX. The authors thank Advanced Analysis and Measurement Center of Yunnan University for the sample testing service.

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Author notes

  1. These authors contributed equally: Biaoqi Liu, Youwei Wu, Dingmei Qin

Authors and Affiliations

  1. Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, and School of Pharmacy, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, 650000, P. R. China

    Biaoqi Liu, Hairong Wang, Weilie Xiao, Xiaoli Li & Ruihan Zhang

  2. College of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, 650000, P. R. China

    Youwei Wu, Dingmei Qin, Hongjie Chen, Yi Zhang & Ruirui Wang

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  1. Biaoqi Liu
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Correspondence to Xiaoli Li, Ruirui Wang or Ruihan Zhang.

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Liu, B., Wu, Y., Qin, D. et al. Discovery of deguelin derivatives in combination with fluconazole against drug-resistant Candida albicans. Med Chem Res 32, 2196–2207 (2023). https://doi.org/10.1007/s00044-023-03118-7

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  • DOI: https://doi.org/10.1007/s00044-023-03118-7

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