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Biochemical and metabolomic insights into antifungal mechanism of berberine against Candida glabrata

  • Applied Microbial and Cell Physiology
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Abstract

An unprecedented expansion of antifungal therapy failure incidences in healthcare settings of Candida glabrata is the matter of global concern that needs to be addressed efficiently and effectively. In this pursuit, the present study has investigated the antifungal mechanism of benzylisoquinoline alkaloid berberine using biochemical, metabolic, and gene expression analysis, with the aim to delineate its therapeutic activity against C. glabrata and differentially fluconazole-responsive clinical isolates. Interestingly, the clinical isolates were found to be highly susceptible to berberine. Berberine was found to control the surface properties like hydrophobicity and charge of the cells. The cell membrane composition was altered by berberine, where the ergosterol and fatty acids were affected. The efflux pump activity was inhibited, and osmotic stress was generated in C. glabrata cells upon berberine exposure. The berberine has also generated oxidative stress and activated antioxidant system in C. glabrata cells. Furthermore, these observations were supported by the transcriptional expression study of C. glabrata cell genes (CDR1, RLM1, SLT2, SUR4, KRE1) and metabolomics analysis. Based on fold change analysis, the study identified 20 differential metabolites upon berberine treatment, which belong to central carbon, amino acids, and nucleotide pathways. The checkerboard analysis revealed the potentiation of some classically used antifungal drugs by berberine, thus suggesting it as a combinatorial nutraceutical adjuvant for the eradication of fungal infections.

Key points

• Berberine exhibited better potency against azole-resistant clinical isolates

• Berberine modulated metabolites of different pathways

• Berberine generated oxidative stress and blocked efflux pump activity

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

PG acknowledges financial support from the Department of Biotechnology (DBT), Government of India, under DBT-RAship scheme. HG acknowledges All India Council for Technical Education (AICTE) for support through QIP scheme. KMP acknowledge the receipt of Grant CRG/2022/003028 and STR/2022/000008 from SERB-DST, from Government of India. Both PG and KMP also acknowledge the technical and financial support under the collaborative alliance of IITR@175 from IIT-Roorkee. The authors are thankful to the NMR and analytical facilities at Institute Instrumentation Centre (IIC) at IIT Roorkee.

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  1. Payal Gupta and Hrishikesh Gupta contributed equally to this work.

Authors and Affiliations

  1. Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee (IIT-Roorkee), Roorkee, 247667, Uttarakhand, India

    Payal Gupta, Hrishikesh Gupta, Shweta Tripathi & Krishna Mohan Poluri

  2. Department of Biotechnology, Graphic Era (Deemed To Be University), Dehradun, 248002, Uttarakhand, India

    Payal Gupta

  3. Centre for Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India

    Krishna Mohan Poluri

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  1. Payal Gupta
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Contributions

KMP conceived the research plan. PG, HG, and ST performed the experiments; PG and HG analyzed the data; PG, HG, and KMP wrote the manuscript. All the authors have read and confirmed the final version of the manuscript. Both the authors PG and HG have contributed equally to the manuscript.

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Correspondence to Krishna Mohan Poluri.

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Gupta, P., Gupta, H., Tripathi, S. et al. Biochemical and metabolomic insights into antifungal mechanism of berberine against Candida glabrata. Appl Microbiol Biotechnol 107, 6085–6102 (2023). https://doi.org/10.1007/s00253-023-12714-x

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