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

  • Clinical Microbiology - Research Paper
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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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Authors and Affiliations

  1. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai, 200025, China

    Ling-Ning Meng, Yu-Ting Wang & Ming-Jie Xiang

  2. Department of Laboratory Medicine, Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Ling-Ning Meng, Jin-Yan Liu, Yu-Ting Wang & Ming-Jie Xiang

  3. Cancer Institute of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725 South Wanping Rd., Shanghai, 200032, China

    Shuai-Shuai Ni

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  1. Ling-Ning Meng
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  2. Jin-Yan Liu
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Correspondence to Shuai-Shuai Ni or Ming-Jie Xiang.

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Meng, LN., Liu, JY., Wang, YT. et al. The discovery of potential phosphopantetheinyl transferase Ppt2 inhibitors against drug-resistant Candida albicans. Braz J Microbiol 51, 1665–1672 (2020). https://doi.org/10.1007/s42770-020-00318-w

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  • DOI: https://doi.org/10.1007/s42770-020-00318-w

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