Lepidine B & E as New Target Inhibitors from Lepidium Sativum Seeds Against Four Enzymes of the Pathogen Candida albicans: In Vitro and In Silico Studies

Author(s): Safia Gacemi*, Khedidja Benarous, Santiago Imperial, Mohamed Yousfi.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 20 , Issue 1 , 2020

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Graphical Abstract:


Abstract:

Background and Objective: The present paper aims to study the inhibition of Candida albicans growth as candidiasis treatment, using seeds of Lepidium sativum as source.

Methods: In vitro assays were carried out on the antifungal activity of three kinds of extracts from L. sativum seeds against four strains of C. albicans, then testing the same phytochemicals on the inhibition of Lipase (LCR). A new in silico study was achieved using molecular docking, with Autodock vina program, to find binding affinity of two important and major lepidine alkaloids (lepidine E and B) towards the four enzymes secreted by C. albicans as target drugs, responsible of vitality and virulence of this yeast cells: Lipase, Serine/threonine phosphatase, Phosphomannose isomerase and Sterol 14-alpha demethylase (CYP51).

Results: The results of the microdillution assay show that the hexanic and alkaloidal extracts have an antifungal activity with MICs: 2.25 mg/ml and 4.5mg/ml, respectively. However, Candida rugosa lipase assay gives a remarkable IC50 values for the hexanic extract (1.42± 0.04 mg/ml) followed by 1.7± 0.1 and 2.29 ± 0.09 mg/ml of ethyl acetate and alkaloidal extracts respectively. The molecular docking confirms a significant correlation between C. albicans growth and inhibition of crucial enzymes involved in the invasion mechanism and cellular metabolisms, for the first time there were an interesting and new positive results on binding modes of lepidine E and B on the four studied enzymes.

Conclusion: Through this work, we propose Lepidine B & E as potent antifungal drugs.

Keywords: Lepidium sativum seed, Lipase, anti-fungal, lepidine alkaloids, molecular docking, Candida albicans.

[1]
Rathod, T.; Padalia, H.; Chanda, S. The potential of plant extracts against multidrug resistant Candida species- A review. The Battle Against Microbial Pathogens: Basic Science.,, 2015, 246-256.
[2]
Weerasekera, M.M.; Wijesinghe, G.K.; Jayarathna, T.A.; Gunasekara, C.P.; Fernando, N.; Kottegoda, N.; Samaranayake, L.P. Culture media profoundly affect Candida albicans and Candida tropicalis growth, adhesion and biofilm development. Mem. Inst. Oswaldo Cruz, 2016, 111(11), 697-702.
[http://dx.doi.org/10.1590/0074-02760160294] [PMID: 27706381]
[3]
Ben-Ami, R. Treatment of Invasive Candidiasis: A Narrative Review. J. Fungi (Basel), 2018, 4(3), 97.
[http://dx.doi.org/10.3390/jof4030097] [PMID: 30115843]
[4]
Hassani Abharian, P.; Dehgha, P.; Hassani Abharian, P.; Tolouei, S. Molecular characterization of Candida dubliniensis and Candida albicans in the oral cavity of drug abusers using duplex polymerase chain reaction. Curr med mycol., 2018, 1, 12-18.
[http://dx.doi.org/10.18502/cmm.4.1.29]
[5]
Molero, G.; Díez-Orejas, R.; Navarro-García, F.; Monteoliva, L.; Pla, J.; Gil, C.; Sánchez-Pérez, M.; Nombela, C. Candida albicans: genetics, dimorphism and pathogenicity. Int. Microbiol., 1998, 1(2), 95-106.
[PMID: 10943347]
[6]
Nasution, A. I. Virulence factor and pathogenicity of Candida albicans in Oral candidiasis. World journal of dentistry., 2013, 4, 267-271.
[PMID: 10.5005/jp-journals-10015-1243]
[7]
Pereira, C.A.; Borges, A.C.; Costa, P.; Silva, M.P.; Back-Britoand, G.N.; Jorge, A.O.C. Candida albicans and virulence factors that increases its pathogenicity. The Battle Against Microbial Pathogens: Basic Science., 2015, 631-636.
[8]
Gácser, A.; Stehr, F.; Kröger, C.; Kredics, L.; Schäfer, W.; Nosanchuk, J.D. Lipase 8 affects the pathogenesis of Candida albicans. Infect. Immun., 2007, 75(10), 4710-4718.
[http://dx.doi.org/10.1128/IAI.00372-07] [PMID: 17646357]
[9]
Mayer, F.L.; Wilson, D.; Hube, B. Candida albicans pathogenicity mechanisms. Virulence, 2013, 4(2), 119-128.
[http://dx.doi.org/10.4161/viru.22913] [PMID: 23302789]
[10]
Benarous, K.; Bombarda, I.; Iriepa, I.; Moraleda, I.; Gaetan, H.; Linani, A.; Tahri, D.; Sebaa, M.; Yousfi, M. Harmaline and hispidin from Peganum harmala and Inonotus hispidus with binding affinity to Candida rugosa lipase: In silico and in vitro studies. Bioorg. Chem., 2015, 62, 1-7.
[http://dx.doi.org/10.1016/j.bioorg.2015.06.005] [PMID: 26151548]
[11]
Ismail, T.; Fatima, N.; Muhammad, S.A.; Zaidi, S.S.; Rehman, N.; Hussain, I.; Tariq, N.U.S.; Amirzada, I.; Mannan, A. Prioritizing and modelling of putative drug target proteins of Candida albicans by systems biology approach. Acta Biochim. Pol., 2018, 65(2), 209-218.
[http://dx.doi.org/10.18388/abp.2017_2327] [PMID: 29913479]
[12]
Lamb, D.C.; Kelly, D.E.; Baldwin, B.C.; Gozzo, F.; Boscott, P.; Richards, W.G.; Kelly, S.L. Differential inhibition of Candida albicans CYP51 with azole antifungal stereoisomers. FEMS Microbiol. Lett., 1997, 149(1), 25-30.
[http://dx.doi.org/10.1111/j.1574-6968.1997.tb10303.x] [PMID: 9103974]
[13]
Roux, C.; Bhatt, F.; Foret, J.; de Courcy, B.; Gresh, N.; Piquemal, J.P.; Jeffery, C.J.; Salmon, L. The reaction mechanism of type I phosphomannose isomerases: new information from inhibition and polarizable molecular mechanics studies. Proteins, 2011, 79(1), 203-220.
[http://dx.doi.org/10.1002/prot.22873] [PMID: 21058398]
[14]
Chen, E.; Choy, M.S.; Petrényi, K.; Kónya, Z.; Erdődi, F.; Dombrádi, V.; Peti, W.; Page, R. Choy, M. S.; Petrényi, K.; Kónya, Z.; Erdődi, F.; Dombrádi, V.;... & Page, R. Molecular insights into the fungus-specific serine/threonine protein phosphatase Z1 in Candida albicans. MBio, 2016, 7(4), e00872-e16.
[http://dx.doi.org/10.1128/mBio.00872-16] [PMID: 27578752]
[15]
Márkus, B.; Szabó, K.; Pfliegler, W.P.; Petrényi, K.; Boros, E.; Pócsi, I.; Tőzsér, J.; Csősz, É.; Dombrádi, V. Proteomic analysis of protein phosphatase Z1 from Candida albicans. PLoS One, 2017, 12(8)e0183176
[http://dx.doi.org/10.1371/journal.pone.0183176] [PMID: 28837603]
[16]
Hargrove, T.Y.; Friggeri, L.; Wawrzak, Z.; Qi, A.; Hoekstra, W.J.; Schotzinger, R.J.; York, J.D.; Guengerich, F.P.; Lepesheva, G.I. Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis. J. Biol. Chem., 2017, 292(16), 6728-6743.
[http://dx.doi.org/10.1074/jbc.M117.778308] [PMID: 28258218]
[17]
Ahmad, I.; Aqil, F.; Owais, M. Modern Phytomedicine., 2006.
[http://dx.doi.org/10.1002/9783527609987]
[18]
Gurib-Fakim, A. Medicinal plants: Traditions of yesterday and drugs of tomorrow; Elsevier, 2006, 27, pp. (1)1-93.
[http://dx.doi.org/10.1016/j.mam.2005.07.008]
[19]
Abdelghany, A. M.; Meikhail, M. S; Abdelraheem, G. E. A.; Badr, S. I.; Elsheshtawy, N. Lepidium sativum natural seed plant extract in the structural and physical characteristics of polyvinyl alcohol. Inter Jour envIronStu., 2018, 13
[http://dx.doi.org/10.1080/00207233.2018.1479564]
[20]
Sekkoum, k.; Cheriti, A.; Taleb, S.; Bourmita, Y. Belboukhari, N. Traditional phototherapy for urinary diseases in Bechar district (south west of Algeria). Elect jour environ agricul and food chem., 2011, 10(8), 2616-2622.
[21]
Rehman, N.; Khan, A.; Alkharfy, K.M.; Gilani, A. Pharmacological Basis for the Medicinal Use of Lepidium sativum in Airways Disorders. Evid. Based Complement. Alternat. Med., 2012, 8.
[http://dx.doi.org/10.1155/2012/596524]
[22]
Wadhwa, S.; Panwar, M. S.; Agrawal, A.; Saini, N.; Patidar, L. L. Patidar, N. A review on pharmacognostical study of Lepidium sativum. Advance research in pharmaceuticals and biologicals., 2012, 2(IV), 316-323.
[23]
Chatoui, K.; Talbaoui, A.; Aneb, M.; Bakri, Y.; Harhar, H.; Tabyaoui, M. Phytochemical Screening, Antioxidant and Antibacterial activity of Lepidium sativum seeds from Morocco. J. Mater. Environ. Sci, 2016, 7(8), 2938-2946.
[24]
Adam, S.I.Y.; Salih, S.A.M.; Abdelgadir, W.S. In vitro Antimicrobial Assessment of Lepidium sativum L. Seeds Extracts. Asian J. Med. Sci, 2011, 3(6), 261-266.
[25]
Ahmad, R.; Mujeeb, M.; Anwar, F.; Husain, A.; Ahmad, A.; Sharma, S. Pharmacognostical and phytochemical analysis of Lepidium sativum L. seeds. ICPJ, 2015, 4(10), 442-446.
[http://dx.doi.org/10.3329/icpj.v4i10.24913]
[26]
Alqahtani, F.Y.; Aleanizy, F.S.; Mahmoud, A.Z.; Farshori, N.N.; Alfaraj, R.; Al-sheddi, E.S.; Alsarra, I.A. Chemical composition and antimicrobial, antioxidant, and anti-inflammatory activities of Lepidium sativum seed oil. Saudi J. Biol. Sci., 2018, •••
[http://dx.doi.org/10.1016/j.sjbs.2018.05.007] [PMID: 31303845]
[27]
Bhasin, P.; Bansal, D.; Punia, A.; Sehrawat, A.R. Antimicrobial activities of Lepidium sativum: Medicinal plant used in folklore remedies in India. J. Pharm. Res., 2012, 5(3), 1643-1645.
[28]
Doke, S.; Guha, M. Garden cress (Lepidium sativum L.) Seed - An Important Medicinal Source: A Review. J. Nat. Prod. Plant Resour, 2014, 4(1), 69-80.
[29]
Maier, U.H.; Gundlach, H.; Zenk, M.H. Seven imidazole alkaloids from Lepidium sativum. Phytochemistry, 1998, 49(6), 1791-1795.
[http://dx.doi.org/10.1016/S0031-9422(98)00275-1] [PMID: 11711103]
[30]
Ferreira, M.R.A.; Santiago, R.R.; Langassner, S.M.Z. Palazzo de Mello. J.C.; Svidzinski, T.I.E.; Soares, L.A.L. Antifungal activity of medicinal plants from Northeastern Brazil. J. Med. Plants Res., 2013, 7(40), 3008-3013.
[http://dx.doi.org/10.5897/JMPR2013.5035]
[31]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The Protein Data Bank. Nucleic Acids Res., 2000, 28(1), 235-242. [Jan].
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[32]
Zhang, M.; Yogesha, S.D.; Mayfield, J.E.; Gill, G.N.; Zhang, Y. Viewing serine/threonine protein phosphatases through the eyes of drug designers. FEBS J., 2013, 280(19), 4739-4760.
[http://dx.doi.org/10.1111/febs.12481] [PMID: 23937612]
[33]
Grochulski, P.; Bouthillier, F.; Kazlauskas, R.J.; Serreqi, A.N.; Schrag, J.D.; Ziomek, E.; Cygler, M. Analogs of reaction intermediates identify a unique substrate binding site in Candida rugosa lipase. Biochemistry, 1994, 33(12), 3494-3500.
[http://dx.doi.org/10.1021/bi00178a005] [PMID: 8142346]
[34]
Pleiss, J.; Fischer, M.; Schmid, R.D. Anatomy of lipase binding sites: the scissile fatty acid binding site. Chem. Phys. Lipids, 1998, 93(1-2), 67-80.
[http://dx.doi.org/10.1016/S0009-3084(98)00030-9] [PMID: 9720251]
[35]
Schmitt, J.; Brocca, S.; Schmid, R.D.; Pleiss, J. Blocking the tunnel: engineering of Candida rugosa lipase mutants with short chain length specificity. Protein Eng., 2002, 15(7), 595-601.
[http://dx.doi.org/10.1093/protein/15.7.595] [PMID: 12200542]
[36]
Ahmad, L.; Plancqueel, S.; Dubosclard, V.; Lazar, N.; Ghattas, W.; Li de la Sierra-Gallay, I.; van Tilbeurgh, H.; Salmon, L. Crystal structure of phosphomannose isomerase from Candida albicans complexed with 5-phospho-d-arabinonhydrazide. FEBS Lett., 2018, 592(10), 1667-1680.
[http://dx.doi.org/10.1002/1873-3468.13059] [PMID: 29687459]
[37]
Shukla, A.; Singh, C.S.; Bigoniya, P. Phytochemical and CNS activity of Lepidium sativum Linn. seeds total alkaloid. Der Pharm. Lett., 2011, 3(2), 226-237.
[38]
Kwapong, A.A.; Stapleton, P.; Gibbons, S. A new dimeric imidazole alkaloid plasmid conjugation inhibitor from Lepidium sativum. Tetrahedron Lett., 2018, 59(20), 1952-1954.
[http://dx.doi.org/10.1016/j.tetlet.2018.04.028]
[39]
Kim, S.; Thiessen, P.A.; Bolton, E.E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B.A.; Wang, J.; Yu, B.; Zhang, J.; Bryant, S.H. PubChem Substance and Compound databases. Nucleic Acids Res., 2016, 44(D1), D1202-D1213.
[http://dx.doi.org/10.1093/nar/gkv951] [PMID: 26400175]
[40]
Bencurova, E.; Gupta, S.; Sarukhanyan, E.; Dandekar, T. Identification of Antifungal Targets Based on Computer Modeling. J. Fungi (Basel), 2018, 4(3)
[http://dx.doi.org/10.3390/jof4030081]
[41]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[http://dx.doi.org/10.1002/jcc.21334] [PMID: 19499576]
[42]
Martins, C.; Carreiras, M.C.; León, R.; de los Ríos, C.; Bartolini, M.; Andrisano, V.; Iriepa, I.; Moraleda, I.; Gálvez, E.; García, M.; Egea, J.; Samadi, A.; Chioua, M.; Marco-Contelles, J. Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues. Eur. J. Med. Chem., 2011, 46(12), 6119-6130.
[http://dx.doi.org/10.1016/j.ejmech.2011.09.038] [PMID: 22000936]
[43]
Zhiri, A.; Baudoux, D. Huiles Essentielles Chémotypées Et Leurs Synergies., 2005.
[44]
Macheix, J.J.; Fleurit, A.; Sarni-Manchado, P. Sarni-Manchado, P.; Cheynier, V. Les polyphénols en agroalimentaire. 2006, 2.
[45]
Negi, S. Exploring Plant and Agro-industrial Wastes for Antimicrobial Biochemicals Biotransformation of Waste Biomass into High Value Biochemicals., 2014, 335-365.
[46]
Cseke, L.J.; Setzer, W.N.; Vogler, B.; Kirakosyan, A.; Kaufman, P.B. Traditional, Analytical, and Preparative Separations of Natural Products.Cseke, L. J.; Kirakosyan, A.; Kaufman, P. B., Warber, S.L.; Duke, J. A.; Brielmann, H. L. Natural products from plants. 2nd ED, 2006, 263.
[47]
Tiwari, P.; Kumar, B.; Kaur, M.; Kaur, G.; Kaur, H. Phytochemical screening and extraction: A review. Internationale pharmaceutica sciencia, 2011, 1, 98-106.
[48]
Seidel, V. Initial and bulk extraction of natural products isolation. Methods Mol. Biol., 2012, 864, 27-41.
[http://dx.doi.org/10.1007/978-1-61779-624-1_2] [PMID: 22367892]
[49]
Jones, W.P.; Kinghorn, A.D. Extraction of Plant Secondary Metabolites Natural Products Isolation. Methods Mol. Biol., 2012, 864, 342-366.
[http://dx.doi.org/10.1007/978-1-61779-624-1_13]
[50]
Sadik, O.; Gheorghe, I.; Chifiriuc, M.C. Virulence and pathogenicity aspects in Candida albicans infections. Rev. Biol. Biomed. Sci, 2018, 1(1), 11-16.
[http://dx.doi.org/10.31178/rbbs.2018.1.1.2]
[51]
Arif, T.; Bhosale, J.D.; Kumar, N.; Mandal, T.K.; Bendre, R.S.; Lavekar, G.S.; Dabur, R. Natural products--antifungal agents derived from plants. J. Asian Nat. Prod. Res., 2009, 11(7), 621-638.
[http://dx.doi.org/10.1080/10286020902942350] [PMID: 20183299]
[52]
Doddanna, S.J.; Patel, S.; Sundarrao, M.A.; Veerabhadrappa, R.S. Antimicrobial activity of plant extracts on Candida albicans: an in vitro study. Indian J. Dent. Res., 2013, 24(4), 401-405.
[http://dx.doi.org/10.4103/0970-9290.118358] [PMID: 24047829]
[53]
Ríos, J.L.; Recio, M.C. Medicinal plants and antimicrobial activity. J. Ethnopharmacol., 2005, 100(1-2), 80-84.
[http://dx.doi.org/10.1016/j.jep.2005.04.025] [PMID: 15964727]
[54]
Routray, W.; Orsat, V. Preparative Extraction and Separation of Phenolic Compounds. Natu products., 2013, 2014-2037.
[55]
Rathod, T.; Padalia, H.; Chanda, S. The potential of plant extracts against multidrug resistant Candida species- A review. The Battle Against Microbial Pathogens: Techn Advan Educational Programs,, 2015, 246-256.
[56]
M., Ahmed; M., Abeen; M., Jehan; N., Ahmad; S., Qayum; M., Marwat; I., Arch Antimicrobial screening of selected flora of Pakistan Biol. Sci., 2011, 63(3), 691-695.
[http://dx.doi.org/10.2298/ABS1103691Z]
[57]
Masomi, F.; Hassanshahian, M. Antimicrobial Activity of Five Medicinal Plants on Candida albicans. Iranian Journal of Toxicolog, 2016, 10(6), 39-43.
[http://dx.doi.org/10.29252/arakmu.10.6.39]
[58]
Sandip, B.G.; Palak, S.; Mahesh, S. V.; Hitesh, A.S.; Hitesh, P.; Dhanji, R.; Dhanji, R. Antimicrobial and antimalarial activities of some selected ethno-medicinal plants used by tribal communities of tapi district, GUJARAT, INDIA. International research journal of pharmacy., 2018, 9(10), 151. 156.10.7897/2230-8407.0910243
[http://dx.doi.org/]
[59]
Erdemoglu, N.; Oskan, S.; Tosun, F. Alkaloid profile and antimicrobial activity of Lupinus angustifolius L. alkaoild extract. Photochemistry reviews., 2006.
[http://dx.doi.org/10.1007/s11101-006-9055-8]
[60]
Dhamgaye, S.; Devaux, F.; Vandeputte, P.; Khandelwal, N.K.; Sanglard, D.; Mukhopadhyay, G.; Prasad, R. Molecular mechanisms of action of herbal antifungal alkaloid berberine, in Candida albicans. PLoS One, 2014, 9(8)e104554
[http://dx.doi.org/10.1371/journal.pone.0104554] [PMID: 25105295]
[61]
Abuelgasim, A.I.; Ali, M.I.; Hassan, A. Antimicrobial activities of extracts for some of medicinal plants. InterJour Advan Applied Scien, 2015, 2(2), 1-5.
[62]
Aqil, F.; Zahin, M.; Ahmad, I.; Owais, M.; Sajjad, M.; Khan, A.; Bansal, S.S.; Farooq, S. Antifungal Activity of Medicinal Plant Extracts and Phytocompounds. A Review., 2010, 449-484.
[http://dx.doi.org/10.1007/978-3-642-12173-9_19]
[63]
Schaller, M.; Borelli, C.; Korting, H.C.; Hube, B. Hydrolytic enzymes as virulence factors of Candida albicans. Mycoses, 2005, 48(6), 365-377.
[http://dx.doi.org/10.1111/j.1439-0507.2005.01165.x] [PMID: 16262871]
[64]
Seyedan, A.; Alshawsh, M.A.; Alshagga, M.A.; Koosha, S.; Mohamed, Z. Medicinal Plants and Their Inhibitory Activities against Pancreatic Lipase: A Review. Evid. Based Complement. Alternat. Med., 2015. 2015973143
[http://dx.doi.org/10.1155/2015/973143] [PMID: 26640503]
[65]
Benarous, K.; Djeridane, A.; Kameli, A.; Yousfi, M. Inhibition of Candida rugosa Lipase by Secondary Metabolites Extracts of Three Algerian Plants and their Antioxydant Activities. Curr. Enzym. Inhib., 2013, 9(1), 75-82.
[http://dx.doi.org/10.2174/1573408011309010010]
[66]
Briones, A.T.; Chichioco-Hernandez, C.L. Lipase inhibitory activity of Carica papaya, Chrysophyllum cainito, Corcorus olitorius, Cympogon citrates and Syzygium cumini extracts. Food Res., 2018, 2(1), 51-55.
[http://dx.doi.org/10.26656/fr.2017.2(1).118]
[67]
Kadeppagari, R.K. lipase inhibitors from plants and their medical applications. Int. J. Pharm. Pharm. Sci., 2015, 7(1), 1-5.
[68]
Benarous, K.; Salemi, R.; Zakhrouf, H. In silico and in vitro studies of Candida rugosa lipase inhibition using amentoflavone and plantagoguanidinic acid from origanum marjorana and Plantago ciliate. Pharmacologyonline, 2017, 2, 205-212.
[69]
Belfeki, H.; Mejri, M.; Hassouna, M. Antioxidant and anti-lipases activities in vitro of Mentha viridis and Eucalyptus globulus extracts. Ind. Crops Prod., 2016, 89, 514-521.
[http://dx.doi.org/10.1016/j.indcrop.2016.06.002]


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VOLUME: 20
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Year: 2020
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DOI: 10.2174/1871530319666190415141520
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