Two natural molecules preferentially inhibit azole-resistant Candida albicans with MDR1 hyperactivation.
10.1016/S1875-5364(19)30023-8
- Author:
Hong-Zhuo SHI
1
;
Wen-Qiang CHANG
1
;
Ming ZHANG
1
;
Hong-Xiang LOU
2
Author Information
1. Department of Natural Product Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
2. Department of Natural Product Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China. Electronic address: louhongxiang@sdu.edu.cn.
- Publication Type:Journal Article
- Keywords:
Azole resistance;
Candida albicans;
Co-culture;
MDR1
- MeSH:
ATP-Binding Cassette Transporters;
genetics;
metabolism;
Antifungal Agents;
chemistry;
metabolism;
pharmacology;
Azoles;
pharmacology;
Biosynthetic Pathways;
drug effects;
genetics;
Candida albicans;
chemistry;
drug effects;
metabolism;
Cell Membrane;
chemistry;
metabolism;
Coculture Techniques;
Drug Resistance, Fungal;
drug effects;
Ergosterol;
metabolism;
Fungal Proteins;
genetics;
metabolism;
Lipids;
chemistry;
Molecular Structure;
Permeability;
Phenyl Ethers;
chemistry;
metabolism;
pharmacology;
Sterols;
chemistry;
metabolism;
Stilbenes;
chemistry;
metabolism;
pharmacology;
Triterpenes;
chemistry;
metabolism;
pharmacology
- From:
Chinese Journal of Natural Medicines (English Ed.)
2019;17(3):209-217
- CountryChina
- Language:English
-
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.
