The discovery of potential phosphopantetheinyl transferase Ppt2 inhibitors against drug-resistant Candida albicans

Abstract

With the high-frequency use or abuse of antifungal drugs, the crisis of drug-resistant fungi continues to increase worldwide; in particular, the infection of drug-resistant Candida albicans brings the great challenge to the clinical treatment. Therefore, to decelerate the spread of this resistance, it is extremely urgent to facilitate the new antifungal targets with novel drugs. Phosphopantetheinyl transferases PPTases (Ppt2 in Candida albicans) had been identified in bacterium and fungi and mammals, effects as a vital enzyme in the metabolism of organisms in C. albicans. Ppt2 transfers the phosphopantetheinyl group of coenzyme A to the acyl carrier protein Acp1 in mitochondria for the synthesis of lipoic acid that is essential for fungal respiration, so making Ppt2 an ideal target for antifungal drugs. In this study, 110 FDA-approved drugs were utilized to investigate the Ppt2 inhibition against drug-resistant Candida albicans by the improved fluorescence polarization experiments, which have enough druggability and structural variety under the novel strategy of drug repurposing. Thereinto, eight agents revealed the favourable Ppt2 inhibitory activities. Further, broth microdilution assay of incubating C. albicans with these eight drugs showed that pterostilbene, procyanidine, dichlorophen and tea polyphenol had the superior MIC values. In summary, these findings provide more valuable insight into the treatment of drug-resistant C. albicans.

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Acknowledgements

The authors thank Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology for kindly providing the clinical drugs. The authors also thank Jiangye Chen of State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences for providing strain BWP17.

Funding

This work was financed by grants from the Program of the National Nature Science Foundation of China (#81871706#), the Program of Shanghai Key Specialty (#ZK2012A21) and the Program of Shanghai Municipal Health and Planning Committee (#201740069) and (#201840227).

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Correspondence to Shuai-Shuai Ni or Ming-Jie Xiang.

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Meng, L., Liu, J., Wang, Y. et al. The discovery of potential phosphopantetheinyl transferase Ppt2 inhibitors against drug-resistant Candida albicans. Braz J Microbiol (2020). https://doi.org/10.1007/s42770-020-00318-w

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Keywords

  • Phosphopantetheinyl transferases PPTases
  • Ppt2 inhibitor
  • Drug-resistant Candida albicans