Fungicidal action of geraniol against Candida albicans is potentiated by abrogated CaCdr1p drug efflux and fluconazole synergism

Among the several mechanisms of multidrug resistance (MDR), overexpression of drug efflux pumps CaCdr1p and CaMdr1p belonging to ATP binding cassette (ABC) and major facilitator superfamily (MFS) respectively remain the predominant mechanisms of candidal infections. Therefore inhibiting or modulatin...

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Bibliographic Details
Published in:PloS one 2018-08, Vol.13 (8), p.e0203079
Main Authors: Singh, Shweta, Fatima, Zeeshan, Ahmad, Kamal, Hameed, Saif
Format: Article
Language:English
Subjects:
Antifungal activity
Antifungal agents
Antimicrobial agents
Biofilms
Biology and Life Sciences
Biotechnology
Candida albicans
Candidiasis
Care and treatment
Cell adhesion
Chloride
Combinatorial analysis
Complementarity-determining region 1
Confocal microscopy
Drug resistance
Efflux
Ergosterol
Fluconazole
Fungicides
Gene expression
Glycerol
Infections
Laboratories
Medicine and Health Sciences
Microscopy
Mitochondria
Molecular docking
Multidrug resistance
Phospholipase
Polymerase chain reaction
Potassium
Research and Analysis Methods
Rhodamine 6G
Sodium
Synergism
Virulence
Yeast
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Summary:Among the several mechanisms of multidrug resistance (MDR), overexpression of drug efflux pumps CaCdr1p and CaMdr1p belonging to ATP binding cassette (ABC) and major facilitator superfamily (MFS) respectively remain the predominant mechanisms of candidal infections. Therefore inhibiting or modulating the function of these transporters continues to draw attention as effective strategy to combat MDR. We have previously reported the antifungal potential of Geraniol (Ger), a natural monoterpenoid from Palmarosa oil, against Candida albicans. Herein, we explored the fungicidal nature of Ger. The Rhodamine 6G (R6G) and Nile red accumulation confirms the specific effect on CaCdr1p. Mechanistic insights with Candida cells overexpressing CaCdr1p and CaMdr1p revealed that Ger specifically modulates CaCdr1p activity. Kinetic studies further unraveled the competitive inhibition of Ger for R6G efflux as evident from increased apparent Km without affecting Vmax value. The effect of Ger on CaCdr1p was substantiated by molecular docking analyses, which depicted in-silico binding affinity of Ger with CaCdr1p and explored that Ger binds to the active site of CaCdr1p with higher binding energy. Although RT-PCR and western blot revealed no change in expressions of CDR1 and CaCdr1p, confocal microscopy images however depicted CaCdr1p mislocalization in presence of Ger. Interestingly, Ger was synergistic (FICI
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0203079