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Published in: BMC Complementary Medicine and Therapies 1/2017

Open Access 01-12-2017 | Research article

Membrane of Candida albicans as a target of berberine

Authors: Nataša Zorić, Ivan Kosalec, Siniša Tomić, Ivan Bobnjarić, Mario Jug, Toni Vlainić, Josipa Vlainić

Published in: BMC Complementary Medicine and Therapies | Issue 1/2017

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Abstract

Background

We investigated the mechanisms of anti-Candida action of isoquinoline alkaloid berberine, active constituent of medically important plants of Barberry species.

Methods

The effects on membrane, morphological transition, synthesis of ergosterol and the consequent changes in membrane permeability have been studied. Polarization and lipid peroxidation level of the membrane following berberine treatment have been addressed.

Results

Minimal inhibitory concentration (MIC) of berberine against C. albicans was 17.75 μg/mL. Cytotoxic effect of berberine was concentration dependent, and in sub-MIC concentrations inhibit morphological transition of C. albicans cells to its filamentous form. Results showed that berberine affects synthesis of membrane ergosterol dose-dependently and induces increased membrane permeability causing loss of intracellular material to the outer space (DNA/protein leakage). Berberine also caused membrane depolarization and lipid peroxidation of membrane constituents indicating its direct effect on the membrane. Moreover, ROS levels were also increased following berberine treatment indicating further the possibility of membrane damage.

Conclusion

Based on the obtained results it seems that berberine achieves its anti-Candida activity by affecting the cell membrane.
Literature
1.
go back to reference Roser E, Gründemann C, Engels I, Huber R. Antibacterial in vitro effects of preparations from Anthroposophical medicine. BMC Complement Altern Med. 2016; doi:10.1186/s12906-016-1350-3. Roser E, Gründemann C, Engels I, Huber R. Antibacterial in vitro effects of preparations from Anthroposophical medicine. BMC Complement Altern Med. 2016; doi:10.​1186/​s12906-016-1350-3.
2.
go back to reference Blumenthal M. The complete German commission E monographs - therapeutic guide to herbal medicine. Austin, TX: American Botanical Council; 1998. Blumenthal M. The complete German commission E monographs - therapeutic guide to herbal medicine. Austin, TX: American Botanical Council; 1998.
3.
go back to reference Yu HH, Kim KJ, Cha JD, Kim HK, Lee YE, Choi NY, You YOJ. Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. Med Food. 2005; doi:10.1089/jmf.2005.8.454. Yu HH, Kim KJ, Cha JD, Kim HK, Lee YE, Choi NY, You YOJ. Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. Med Food. 2005; doi:10.​1089/​jmf.​2005.​8.​454.
4.
go back to reference Chu M, Xiao R, Yin Y, Wang X, Chu Z, Zhang M, Ding R, Wang Y. Berberine: a medicinal compound for the treatment of bacterial infections. Clin Microbial. 2014; doi:10.4172/2327-5073.1000150. Chu M, Xiao R, Yin Y, Wang X, Chu Z, Zhang M, Ding R, Wang Y. Berberine: a medicinal compound for the treatment of bacterial infections. Clin Microbial. 2014; doi:10.​4172/​2327-5073.​1000150.
5.
go back to reference Han Y, Lee JH. Berberine synergy with amphotericin B against disseminated candidiasis in mice. Biol Pharm Bull. 2005;28(3):541–4.CrossRefPubMed Han Y, Lee JH. Berberine synergy with amphotericin B against disseminated candidiasis in mice. Biol Pharm Bull. 2005;28(3):541–4.CrossRefPubMed
6.
go back to reference Quan H, Cao YY, Xu Z, Zhao JX, Gao PX, Qin XF, Jiang YY. Potent in vitro synergism of fluconazole and berberine chloride against clinical isolates of Candida albicans resistant to fluconazole. Antimicrob Agents Chemother. 2006; doi:10.1128/AAC.50.3.1096-1099.2006. Quan H, Cao YY, Xu Z, Zhao JX, Gao PX, Qin XF, Jiang YY. Potent in vitro synergism of fluconazole and berberine chloride against clinical isolates of Candida albicans resistant to fluconazole. Antimicrob Agents Chemother. 2006; doi:10.​1128/​AAC.​50.​3.​1096-1099.​2006.
9.
go back to reference Dhamgaye S, Devaux F, Vandeputte P, Khandelwal NK, Sanglard D, Mukhopadhyay G, Prasad R. Molecular mechanisms of action of herbal antifungal alkaloid berberine in Candida albicans. PloS ONE. 2014. doi:10.1371/journal.pone.0104554. Dhamgaye S, Devaux F, Vandeputte P, Khandelwal NK, Sanglard D, Mukhopadhyay G, Prasad R. Molecular mechanisms of action of herbal antifungal alkaloid berberine in Candida albicans. PloS ONE. 2014. doi:10.​1371/​journal.​pone.​0104554.
10.
go back to reference da Silva AR, de Andrade Neto JB, da Silva CR, Campos RDS, Costa Silva RA, Freitas DD, do Nascimento FBSA, de Andrade LND, Sampaio LS, Grangeiro TB, Magalhães HIF, Cavalcanti BC, de Moraes MO, Nobre Júnior HV. Berberine antifungal activity in fluconazole-resistant pathogenic yeasts: action mechanism evaluated by flow cytometry and biofilm growth inhibition in Candida spp. Antimicrob Agents Chemother. 2016. doi:10.1128/AAC.01846-15. da Silva AR, de Andrade Neto JB, da Silva CR, Campos RDS, Costa Silva RA, Freitas DD, do Nascimento FBSA, de Andrade LND, Sampaio LS, Grangeiro TB, Magalhães HIF, Cavalcanti BC, de Moraes MO, Nobre Júnior HV. Berberine antifungal activity in fluconazole-resistant pathogenic yeasts: action mechanism evaluated by flow cytometry and biofilm growth inhibition in Candida spp. Antimicrob Agents Chemother. 2016. doi:10.​1128/​AAC.​01846-15.
11.
go back to reference Zorić N, Horvat I, Kopjar N, Vučemilović A. Kremer, Tomić S, Kosalec I. Hydroxytyrosol expresses antifungal activity in vitro. Curr Drug Targets. 2013;14:992–8.CrossRefPubMed Zorić N, Horvat I, Kopjar N, Vučemilović A. Kremer, Tomić S, Kosalec I. Hydroxytyrosol expresses antifungal activity in vitro. Curr Drug Targets. 2013;14:992–8.CrossRefPubMed
12.
go back to reference Zuzarte M, Vale-Silva L, Gonçalves MJ, Cavaleiro C, Vaz S, Canhoto J, Pinto E, Salgueiro L. Antifungal activity of phenolic-rich Lavandula multifida L. essential oil. Eur J Clin Microbiol Infect Dis. 2012. doi:10.1007/s10096-011-1450-4. Zuzarte M, Vale-Silva L, Gonçalves MJ, Cavaleiro C, Vaz S, Canhoto J, Pinto E, Salgueiro L. Antifungal activity of phenolic-rich Lavandula multifida L. essential oil. Eur J Clin Microbiol Infect Dis. 2012. doi:10.​1007/​s10096-011-1450-4.
13.
14.
go back to reference Khan MSA, Ahmad I, Cameotra SS. Phenyl aldehyde and propanoids exert multiple sites of action towards cell membrane and cell wall targeting ergosterol in Candida albicans. AMB Express. 2013; doi:10.1186/2191-0855-3-54. Khan MSA, Ahmad I, Cameotra SS. Phenyl aldehyde and propanoids exert multiple sites of action towards cell membrane and cell wall targeting ergosterol in Candida albicans. AMB Express. 2013; doi:10.​1186/​2191-0855-3-54.
15.
go back to reference Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–75.PubMed Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–75.PubMed
18.
go back to reference Jayatilake JA, Samaranayake YH, Cheung LK, Samaranayake LP. Quantitative evaluation of tissue invasion by wild type, hyphal and SAP mutants of Candida albicans, and non-albicans Candida species in reconstituted human oral epithelium. J Oral Pathol Med. 2006; doi:10.1111/j.1600-0714.2006.00435.x. Jayatilake JA, Samaranayake YH, Cheung LK, Samaranayake LP. Quantitative evaluation of tissue invasion by wild type, hyphal and SAP mutants of Candida albicans, and non-albicans Candida species in reconstituted human oral epithelium. J Oral Pathol Med. 2006; doi:10.​1111/​j.​1600-0714.​2006.​00435.​x.
20.
go back to reference Midkiff J, Borochoff-Porte N, White D, Johnson DI. Small molecule inhibitors of the Candida albicans budded-to-hyphal transition act through multiple signaling pathways. PLoS One. 2011; doi:10.1371/journal.pone.0025395. Midkiff J, Borochoff-Porte N, White D, Johnson DI. Small molecule inhibitors of the Candida albicans budded-to-hyphal transition act through multiple signaling pathways. PLoS One. 2011; doi:10.​1371/​journal.​pone.​0025395.
21.
go back to reference Kosalec I, Puel O, Delaforge M, Kopjar N, Antolovic R, Jelic D, Matica B, Galtier P, Pepeljnjak S. Isolation and cytotoxicity of low-molecular-weight metabolites of Candida albicans. Front Biosci. 2008;13:6893–904.CrossRefPubMed Kosalec I, Puel O, Delaforge M, Kopjar N, Antolovic R, Jelic D, Matica B, Galtier P, Pepeljnjak S. Isolation and cytotoxicity of low-molecular-weight metabolites of Candida albicans. Front Biosci. 2008;13:6893–904.CrossRefPubMed
22.
go back to reference Hitchcock PJ, Brown TM. Morphological heterogeneity among Salmonella lipopolysaccharide chemotypes in silver-stained polyacrylamide gels. J Bacteriol. 1983;154(1):269–77.PubMedPubMedCentral Hitchcock PJ, Brown TM. Morphological heterogeneity among Salmonella lipopolysaccharide chemotypes in silver-stained polyacrylamide gels. J Bacteriol. 1983;154(1):269–77.PubMedPubMedCentral
24.
go back to reference Liao S, Klein MI, Heim KP, Fan Y, Bitoun JP, Ahn SJ, Burne RA, Koo H, Brady LJ, Wen ZT. Streptococcus mutans extracellular DNA is upregulated during growth in biofilms, actively released via membrane vesicles, and influenced by components of the protein secretion machinery. J Bacteriol. 2014;196:2355–66.CrossRefPubMedPubMedCentral Liao S, Klein MI, Heim KP, Fan Y, Bitoun JP, Ahn SJ, Burne RA, Koo H, Brady LJ, Wen ZT. Streptococcus mutans extracellular DNA is upregulated during growth in biofilms, actively released via membrane vesicles, and influenced by components of the protein secretion machinery. J Bacteriol. 2014;196:2355–66.CrossRefPubMedPubMedCentral
26.
go back to reference Aikens J, Dix TA. Hydrodioxyl (perhydroxyl), peroxyl, and hydroxyl radical-initiated lipid peroxidation of large unilamellar vesicles (liposomes): comparative and mechanistic studies. Arch Biochem Biophys. 1993;395:516–25.CrossRef Aikens J, Dix TA. Hydrodioxyl (perhydroxyl), peroxyl, and hydroxyl radical-initiated lipid peroxidation of large unilamellar vesicles (liposomes): comparative and mechanistic studies. Arch Biochem Biophys. 1993;395:516–25.CrossRef
27.
28.
go back to reference Janero DR. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med. 1990;9(6):515–40.CrossRefPubMed Janero DR. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med. 1990;9(6):515–40.CrossRefPubMed
29.
go back to reference Khan H, Saeed M, Khan MA, Khan I, Ahmad M. Muhammad N, Khan A. Antimalarial and free radical scavenging activities of rhizomes of Polygonatum verticillatum supported by isolated metabolites. Med Chem Res 2011. doi: 10.1007/s00044-011-9637-x. Khan H, Saeed M, Khan MA, Khan I, Ahmad M. Muhammad N, Khan A. Antimalarial and free radical scavenging activities of rhizomes of Polygonatum verticillatum supported by isolated metabolites. Med Chem Res 2011. doi: 10.​1007/​s00044-011-9637-x.
30.
go back to reference Missall TA, Lodge JK, McEwen JE. Mechanisms of resistance to oxidative and nitrosative stress: implications for fungal survival in mammalian hosts. Eukaryot Cell. 2004;3:835–46.CrossRefPubMedPubMedCentral Missall TA, Lodge JK, McEwen JE. Mechanisms of resistance to oxidative and nitrosative stress: implications for fungal survival in mammalian hosts. Eukaryot Cell. 2004;3:835–46.CrossRefPubMedPubMedCentral
31.
go back to reference Jazvinšćak Jembrek M, Vlainić J, Radovanović J, Radovanović V, Erhardt J, Oršolić N. Effects of copper overload in P19 neurons: impairment of glutathione redox homeostasis and crosstalk between caspase and calpain protease systems in ROS-induced apoptosis. Biometals. 2014; doi:10.1007/s10534-014-9792-x. Jazvinšćak Jembrek M, Vlainić J, Radovanović J, Radovanović V, Erhardt J, Oršolić N. Effects of copper overload in P19 neurons: impairment of glutathione redox homeostasis and crosstalk between caspase and calpain protease systems in ROS-induced apoptosis. Biometals. 2014; doi:10.​1007/​s10534-014-9792-x.
32.
go back to reference Georgopapadakou NH, Dix BA, Smith SA, Freudenberger J, Funke PT. Effect of antifungal agents on lipid biosynthesis and membrane integrity in Candida albicans. Antimicrob Agents Chemother. 1987;31(1):46–51.CrossRefPubMedPubMedCentral Georgopapadakou NH, Dix BA, Smith SA, Freudenberger J, Funke PT. Effect of antifungal agents on lipid biosynthesis and membrane integrity in Candida albicans. Antimicrob Agents Chemother. 1987;31(1):46–51.CrossRefPubMedPubMedCentral
33.
go back to reference Shao J, Shi G, Wang T, Wu D, Wang C. Antiproliferation of Berberine in combination with Fluconazole from the perspectives of reactive oxygen species, Ergosterol and drug efflux in a Fluconazole-resistant Candida tropicalisIsolate. Front Microbiol. 2016;7:1516.CrossRefPubMedPubMedCentral Shao J, Shi G, Wang T, Wu D, Wang C. Antiproliferation of Berberine in combination with Fluconazole from the perspectives of reactive oxygen species, Ergosterol and drug efflux in a Fluconazole-resistant Candida tropicalisIsolate. Front Microbiol. 2016;7:1516.CrossRefPubMedPubMedCentral
34.
go back to reference Ahmad A, Khan A, Kumar P, Bhatt RP, Manzoor N. Antifungal activity of Coriaria nepalensis essential oil by disrupting ergosterol biosynthesis and membrane integrity against Candida. Yeast. 2011; doi:10.1002/yea.1890. Ahmad A, Khan A, Kumar P, Bhatt RP, Manzoor N. Antifungal activity of Coriaria nepalensis essential oil by disrupting ergosterol biosynthesis and membrane integrity against Candida. Yeast. 2011; doi:10.​1002/​yea.​1890.
Metadata
Title
Membrane of Candida albicans as a target of berberine
Authors
Nataša Zorić
Ivan Kosalec
Siniša Tomić
Ivan Bobnjarić
Mario Jug
Toni Vlainić
Josipa Vlainić
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2017
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-017-1773-5

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