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      Two natural molecules preferentially inhibit azole-resistant Candida albicans with MDR1 hyperactivation

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          Abstract

          Antifungal drug resistance is a significant clinical problem, and antifungal agents that can evade resistance are urgently needed. In infective niches, resistant organisms often co-existed with sensitive ones, or a subpopulation of antibiotic-susceptible organisms may evolve into resistant ones during antibiotic treatment and eventually dominate the whole population. In this study, we established a co-culture assay in which an azole-resistant Candida albicans strain was mixed with a susceptible strain labeled with green fluorescent protein to mimic in vivo conditions and screen for antifungal drugs. Fluconazole was used as a positive control to verify the validity of this co-culture assay. Five natural molecules exhibited antifungal activity against both susceptible and resistant C. albicans. Two of these compounds, retigeric acid B (RAB) and riccardin D (RD), preferentially inhibited C. albicans strains in which the efflux pump MDR1 was activated. This selectivity was attributed to greater intracellular accumulation of the drugs in the resistant strains. Changes in sterol and lipid compositions were observed in the resistant strains compared to the susceptible strain, and might increase cell permeability to RAB and RD. In addition, RAB and RD interfered with the sterol pathway, further aggregating the decrease in ergosterol in the sterol synthesis pathway in the MDR1-activated strains. Our findings here provide an alternative for combating resistant pathogenic fungi.

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          Author and article information

          Journal
          CJNM
          Chinese Journal of Natural Medicines
          Elsevier
          1875-5364
          20 March 2019
          : 17
          : 3
          : 209-217
          Affiliations
          1 Department of Natural Product Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
          Author notes
          *Corresponding author: Tel: 86-531-88382012, Fax: 86-531-88382019; E-mail: louhongxiang@ 123456sdu.edu.cn

          ΔThese authors contributed to the work equally.

          These authors have no conflict of interest to declare.

          Article
          S1875-5364(19)30023-8
          10.1016/S1875-5364(19)30023-8
          Copyright © 2019 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.
          Funding
          Funded by: National Natural Science Foundation
          Award ID: 81630093
          Award ID: 81773786
          Award ID: 81402804
          This work was funded by the National Natural Science Foundation (Nos. 81630093, 81773786, 81402804), and the Young Scholars Program of Shandong University.

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