Vanillin confers antifungal drug synergism in Candida albicans by impeding CaCdr2p driven efflux |
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| Affiliation: | 1. Amity Institute of Biotechnology, Amity university Haryana, Gurugram (Manesar) 122413, India;2. Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India;1. Department of Dermatology, Hospital Institute of Social Hygiene (IHS), BP: 7045, Dakar, Senegal;2. Department of Dermatology, Hospital Aristide Le Dantec (HALD), BP: 3001, Dakar, Senegal;1. Department of Medical Parasitology and Mycology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran;2. Department of Parasitology and Mycology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran;3. Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran;4. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran;5. Department of Medical Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran;6. Medical Mycology, Graduate School of Medicine, Teikyo University, Tokyo, Japan;1. Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran;2. Department of Medical Mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran;3. Antimicrobial Resistance Research Center, Mazandaran University of Medical Sciences, Sari, Iran;4. Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital (CWZ), Nijmegen, The Netherlands;5. Centre of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands;6. Department of Medical Parasitology and Mycology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran;7. Department of Pulmonary and Critical Care, Advanced Thoracic Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran;8. Department of Infectious Diseases and tropical medicines, School of Medicine, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Tehran, Iran;9. Department of Parasitology and Mycology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran;10. Department of Medical Parasitology and Mycology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran;11. Department of Medical Parasitology and Mycology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran;12. Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran;1. Infectious Diseases Department of Centro Hospitalar Universitário do Porto, EPE, Porto, Portugal;2. Internal Medicine Department of Centro Hospitalar Universitário do Porto, EPE, Porto, Portugal;3. Microbiology Department of Centro Hospitalar Universitário do Porto, EPE, Porto, Portugal;4. Pathological Anatomy Department of Centro Hospitalar do Porto, EPE, Porto, Portugal;5. Pediatrics Department of Hospital do Mal de Hansen, Cumura, Guine Bissau;6. Infectious Diseases Department of Hospital do Mal de Hansen, Cumura, Guine Bissau |
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| Abstract: | AimAmong the most common mechanisms of multidrug resistance (MDR) in prevalent human fungal pathogen, Candida albicans, overexpression of drug efflux pumps remains the predominant mechanism. Hence to inhibit efflux pumps and chemosensitize C. albicans against traditional antifungal drugs still represents an attractive approach. The present study aimed to analyze the effect of Vanillin (Van), a natural food flavoring agent, on drug efflux pump activity of Candida albicans.Methods and resultsWe observed that Van specifically inhibits Candida drug resistance protein 2 (CaCdr2p) activity belonging to ATP Binding Cassette (ABC) superfamily as revealed by abrogated rhodamine 6G efflux and nile red accumulation assay with CaCdr2p over expressing strain. Insight studies into the mechanisms suggested that abrogated efflux by CaCdr2p is due to competitive mode of inhibition by Van as depicted by Lineweaver-Burk plot. RT-PCR, western blot and confocal microscopy further unraveled that Van leads to reduced expression of CDR2 and CaCdr2p mislocalization respectively. Furthermore, Van sensitizes the azole sensitive and resistant clinical matched pair of isolates Gu4/Gu5 and led to abrogated rhodamine 6G efflux and depleted ergosterol. Furthermore, Van synergizes with membrane targeting drugs fluconazole and amphotericin B as their fractional inhibitory coefficient index was less than 0.5.ConclusionVan being a potent inhibitor of CaCdr2p and chemosensitizing of drug resistant C. albicans warrants further studies to be exploited as effective antifungal agent. |
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| Keywords: | Vanillin MDR CaCdr2p Ergosterol Drug synergism |
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