title: Molecular mechanisms of action of herbal antifungal alkaloid berberine, in Candida albicans.
abstract: Candida albicans causes superficial to systemic infections in immuno-compromised individuals. The concomitant use of fungistatic drugs and the lack of cidal drugs frequently result in strains that could withstand commonly used antifungals, and display multidrug resistance (MDR). In search of novel fungicidals, in this study, we have explored a plant alkaloid berberine (BER) for its antifungal potential. For this, we screened an in-house transcription factor (TF) mutant library of C. albicans strains towards their susceptibility to BER. Our screen of TF mutant strains identified a heat shock factor (HSF1), which has a central role in thermal adaptation, to be most responsive to BER treatment. Interestingly, HSF1 mutant was not only highly susceptible to BER but also displayed collateral susceptibility towards drugs targeting cell wall (CW) and ergosterol biosynthesis. Notably, BER treatment alone could affect the CW integrity as was evident from the growth retardation of MAP kinase and calcineurin pathway null mutant strains and transmission electron microscopy. However, unlike BER, HSF1 effect on CW appeared to be independent of MAP kinase and Calcineurin pathway genes. Additionally, unlike hsf1 null strain, BER treatment of Candida cells resulted in dysfunctional mitochondria, which was evident from its slow growth in non-fermentative carbon source and poor labeling with mitochondrial membrane potential sensitive probe. This phenotype was reinforced with an enhanced ROS levels coinciding with the up-regulated oxidative stress genes in BER-treated cells. Together, our study not only describes the molecular mechanism of BER fungicidal activity but also unravels a new role of evolutionary conserved HSF1, in MDR of Candida.
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, India; Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Sanjiveeni
authors.initials: S
authors.lastname: Dhamgaye
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 7238, Laboratoire de genomique des microorganisms, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Devaux
authors.affiliation: Institute of Microbiology, University of Lausanne and University Hospital Center, Lausanne, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vandeputte
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Nitesh Kumar
authors.initials: NK
authors.lastname: Khandelwal
authors.affiliation: Institute of Microbiology, University of Lausanne and University Hospital Center, Lausanne, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Sanglard
authors.affiliation: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Gauranga
authors.initials: G
authors.lastname: Mukhopadhyay
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Prasad
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D025141:Drug Resistance, Fungal; D018432:Drug Resistance, Multiple; D005656:Fungal Proteins / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D001599:Berberine
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