title: Quercetin sensitizes fluconazole-resistant candida albicans to induce apoptotic cell death by modulating quorum sensing.
abstract: Quorum sensing (QS) regulates group behaviors of Candida albicans such as biofilm, hyphal growth, and virulence factors. The sesquiterpene alcohol farnesol, a QS molecule produced by C. albicans, is known to regulate the expression of virulence weapons of this fungus. Fluconazole (FCZ) is a broad-spectrum antifungal drug that is used for the treatment of C. albicans infections. While FCZ can be cytotoxic at high concentrations, our results show that at much lower concentrations, quercetin (QC), a dietary flavonoid isolated from an edible lichen (Usnea longissima), can be implemented as a sensitizing agent for FCZ-resistant C. albicans NBC099, enhancing the efficacy of FCZ. QC enhanced FCZ-mediated cell killing of NBC099 and also induced cell death. These experiments indicated that the combined application of both drugs was FCZ dose dependent rather than QC dose dependent. In addition, we found that QC strongly suppressed the production of virulence weapons-biofilm formation, hyphal development, phospholipase, proteinase, esterase, and hemolytic activity. Treatment with QC also increased FCZ-mediated cell death in NBC099 biofilms. Interestingly, we also found that QC enhances the anticandidal activity of FCZ by inducing apoptotic cell death. We have also established that this sensitization is reliant on the farnesol response generated by QC. Molecular docking studies also support this conclusion and suggest that QC can form hydrogen bonds with Gln969, Thr1105, Ser1108, Arg1109, Asn1110, and Gly1061 in the ATP binding pocket of adenylate cyclase. Thus, this QS-mediated combined sensitizer (QC)-anticandidal agent (FCZ) strategy may be a novel way to enhance the efficacy of FCZ-based therapy of C. albicans infections.
authors: Pharmacognosy & Ethnopharmacology Division, CSIR-National Botanical Research Institute, Lucknow, Uttar Pradesh, India rawataks@rediffmail.com dk.upreti@nbri.res.in bn.singh@nbri.res.in.
authors: B N
authors: BN
authors: Singh
authors: Lichenology Laboratory, Plant Biodiversity and Conservation Biology Division, CSIR-National Botanical Research Institute, Lucknow, India rawataks@rediffmail.com dk.upreti@nbri.res.in bn.singh@nbri.res.in.
authors: D K
authors: DK
authors: Upreti
authors: Centre of Excellence in Materials Science (Nanomaterials), Department of Applied Physics, Z. H. College of Engineering & Technology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.
authors: B R
authors: BR
authors: Singh
authors: Pharmacognosy & Ethnopharmacology Division, CSIR-National Botanical Research Institute, Lucknow, Uttar Pradesh, India.
authors: G
authors: G
authors: Pandey
authors: Pharmacognosy & Ethnopharmacology Division, CSIR-National Botanical Research Institute, Lucknow, Uttar Pradesh, India.
authors: S
authors: S
authors: Verma
authors: Department of BioMedical Engineering, Faculty of Electronics and Communication, Brno University of Technology, Brno, Czech Republic.
authors: S
authors: S
authors: Roy
authors: Centre of Excellence in Materials Science (Nanomaterials), Department of Applied Physics, Z. H. College of Engineering & Technology, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.
authors: A H
authors: AH
authors: Naqvi
authors: Pharmacognosy & Ethnopharmacology Division, CSIR-National Botanical Research Institute, Lucknow, Uttar Pradesh, India rawataks@rediffmail.com dk.upreti@nbri.res.in bn.singh@nbri.res.in.
authors: A K S
authors: AK
authors: Rawat
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018441:Biofilms / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects*; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D015725:Fluconazole / Q000494:pharmacology*; D025301:Hyphae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011794:Quercetin / Q000494:pharmacology*; D053038:Quorum Sensing / Q000187:drug effects*; D020949:Usnea / Q000737:chemistry; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D000975:Antioxidants; D037521:Virulence Factors; D015725:Fluconazole; D011794:Quercetin
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