Terrestrial plants have proven to be a prolific producer of clinically effective antimalarial drugs, but the antimalarial potential of seaweeds has been little explored. The main aim of this study was to assess the in vitro chemotherapeutical and prophylactic potential of the extracts of twenty-three seaweeds collected from the south coast of England against blood stage (BS) and liver stage (LS) Plasmodium parasites. The majority (14) of the extracts were active against BS of P. falciparum, with brown seaweeds Cystoseira tamariscifolia, C. baccata and the green seaweed Ulva lactuca being the most active (IC 50s around 3 μg/mL). The extracts generally had high selectivity indices (>10). Eight seaweed extracts inhibited the growth of LS parasites of P. berghei without any obvious effect on the viability of the human hepatoma (Huh7) cells, and the highest potential was exerted by U. lactuca and red seaweeds Ceramium virgatum and Halopitys incurvus (IC 50 values 14.9 to 28.8 μg/mL). The LS-active extracts inhibited one or more key enzymes of the malarial type-II fatty acid biosynthesis (FAS-II) pathway, a drug target specific for LS. Except for the red seaweed Halopitys incurvus, all LS-active extracts showed dual activity versus both malarial intracellular stage parasites. This is the first report of LS antiplasmodial activity and dual stage inhibitory potential of seaweeds.
References
[1]
World Health Organization fact sheet. Available online: http://www.who.int/malaria/publications/world_malaria_report_2012/wmr2012_factsheet.pdf (accessed on 6 August 2013).
[2]
Cox, F.E. History of the discovery of the malaria parasites and their vectors. Parasit Vectors 2010, 3, 5, doi:10.1186/1756-3305-3-5.
[3]
Price, R.N.; Tjitra, E.; Guerra, C.A.; Yeung, S.; White, N.J.; Anstey, N.M. Vivax malaria: Neglected and not benign. Am. J. Trop. Med. Hyg. 2007, 77, 79–87.
[4]
Prudencio, M.; Mota, M.M.; Mendes, A.M. A toolbox to study liver stage malaria. Trends Parasitol. 2011, 27, 565–574, doi:10.1016/j.pt.2011.09.004.
[5]
Derbyshire, E.R.; Prudencio, M.; Mota, M.M.; Clardy, J. Liver-stage malaria parasites vulnerable to diverse chemical scaffolds. Proc. Natl. Acad. Sci. USA 2012, 109, 8511–8516.
[6]
Yu, M.; Kumar, T.R.; Nkrumah, L.J.; Coppi, A.; Retzlaff, S.; Li, C.D.; Kelly, B.J.; Moura, P.A.; Lakshmanan, V.; Freundlich, J.S.; et al. The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites. Cell Host Microbe 2008, 4, 567–578, doi:10.1016/j.chom.2008.11.001.
[7]
Vaughan, A.M.; O’Neill, M.T.; Tarun, A.S.; Camargo, N.; Phuong, T.M.; Aly, A.S.; Cowman, A.F.; Kappe, S.H. Type II fatty acid synthesis is essential only for malaria parasite late liver stage development. Cell Microbiol. 2009, 11, 506–520, doi:10.1111/j.1462-5822.2008.01270.x.
[8]
Surolia, N.; Surolia, A. Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum. Nat. Med. 2001, 7, 167–173, doi:10.1038/84612.
[9]
Tarun, A.S.; Peng, X.; Dumpit, R.F.; Ogata, Y.; Silva-Rivera, H.; Camargo, N.; Daly, T.M.; Bergman, L.W.; Kappe, S.H. A combined transcriptome and proteome survey of malaria parasite liver stages. Proc. Natl. Acad. Sci. USA 2008, 105, 305–310, doi:10.1073/pnas.0710780104.
[10]
Moo-Puc, R.; Robledo, D.; Freile-Pelegrin, Y. Evaluation of selected tropical seaweeds for in vitro anti-trichomonal activity. J. Ethnopharmacol. 2008, 120, 92–97, doi:10.1016/j.jep.2008.07.035.
[11]
Baslow, M.H. Marine Pharmacology; Williams & Wilkins Co: Baltimore, MD, USA, 1969; pp. 69–71.
[12]
Scheuer, P.J. Marine Natural Products, Chemical and Biological Perspectives, 3rd ed. ed.; Academic Press: New York, NY, USA, 1980; pp. 100–106.
[13]
Orhan, I.; Sener, B.; Brun, R.; Perozzo, R; Tasdemir, D. Turkish freshwater and marine macrophyte extracts show in vitro antiprotozoal activity and inhibit FabI, a key enzyme of Plasmodium falciparum fatty acid biosynthesis. Phytomedicine 2006, 13, 388–393, doi:10.1016/j.phymed.2005.10.010.
[14]
Süzge？-Sel？uk, S.; Meri？li, A.H.; Güven, K.C.; Kaiser, M.; Casey, R.; Hingley-Wilson, S.; Lalvani, A.; Tasdemir, D. Evaluation of Turkish seaweeds for antiprotozoal, antimycobacterial and cytotoxic activities. Phytother. Res. 2011, 25, 778–783.
[15]
Spavieri, J.; Kaiser, M.; Casey, R.; Hingley-Wilson, S.; Lalvani, A.; Blunden, G.; Tasdemir, D. Antiprotozoal, antimycobacterial and cytotoxic potential of some British green algae. Phytother. Res. 2010, 24, 1095–1098.
[16]
Allmendinger, A.; Spavieri, J.; Kaiser, M.; Casey, R.; Hingley-Wilson, S.; Lalvani, A.; Guiry, M.; Blunden, G.; Tasdemir, D. Antiprotozoal, antimycobacterial and cytotoxic potential of twenty-three British and Irish red algae. Phytother. Res. 2010, 24, 1099–1103.
[17]
Spavieri, J.; Allmendinger, A.; Kaiser, M.; Casey, R.; Hingley-Wilson, S.; Lalvani, A.; Guiry, M.D.; Blunden, G.; Tasdemir, D. Antimycobacterial, antiprotozoal and cytotoxic potential of twenty-one brown algae (Phaeophyceae) from British and Irish waters. Phytother. Res. 2010, 24, 1724–1729, doi:10.1002/ptr.3208.
[18]
Matile, H.; Pink, J.R.L. Plasmodium falciparum malaria parasite cultures and their use in immunology. In Immunological Methods; Lefkovits, I., Pernis, B., Eds.; Academic Press: San Diego, CA, USA, 1990; pp. 221–234.
[19]
Tasdemir, D.; Lack, G.; Brun, R.; Ruedi, P.; Scapozza, L.; Perozzo, R. Inhibition of Plasmodium falciparum fatty acid biosynthesis: evaluation of FabG, FabZ, and FabI as drug targets for flavonoids. J. Med. Chem. 2006, 49, 3345–3353, doi:10.1021/jm0600545.
[20]
Vonthron-Sénécheau, C; Kaiser, M.; Devambez, I.; Vastel, A.; Mussio, I.; Rusig, A.M. Antiprotozoal activities of organic extracts from French marine seaweeds. Mar. Drugs 2011, 9, 922–933, doi:10.3390/md9060922.
[21]
Ravikumar, S.; Inbaneson, S.J.; Suganthi, P. Seaweeds as a source of lead compounds for the development of new antiplasmodial drugs from South East coast of India. Parasitol. Res. 2011, 109, 47–52, doi:10.1007/s00436-010-2219-x.
[22]
Ravikumar, S.; Inbaneson, S.J.; Suganthi, P.; Gokulakrishnan, R.; Venkatesan, M. In vitro antiplasmodial activity of ethanolic extracts of seaweed macroalgae against Plasmodium falciparum. Parasitol. Res. 2011, 108, 1411–1416, doi:10.1007/s00436-010-2185-3.
[23]
Ravikumar, S.; Ramanathan, G.; Gnanadesigan, M.; Ramu, A.; Vijayakumar, V. In vitro antiplasmodial activity of methanolic extracts from seaweeds of South West Coast of India. Asian Pac. J. Trop. Med. 2011, 4, 862–865, doi:10.1016/S1995-7645(11)60209-5.
[24]
Elsayed, K.N.; Radwan, M.M.; Hassan, S.H.; Abdelhameed, M.S.; Ibraheem, I.B.; Ross, S.A. Phytochemical and biological studies on some Egyptian seaweeds. Nat. Prod. Commun. 2012, 7, 1209–1210.
[25]
Afolayan, A.F.; Mann, M.G.; Lategan, C.A.; Smith, P.J.; Bolton, J.J.; Beukes, D.R. Antiplasmodial halogenated monoterpenes from the marine red alga Plocamium cornutum. Phytochemistry 2009, 70, 597–600, doi:10.1016/j.phytochem.2009.02.010.
[26]
Stout, E.P.; Cervantes, S.; Prudhomme, J.; France, S.; La Clair, J.J.; Le Roch, K.; Kubanek, J. Bromophycolide A targets heme crystallization in the human malaria parasite Plasmodium falciparum. ChemMedChem. 2011, 6, 1572–1577, doi:10.1002/cmdc.201100252.
[27]
Stout, E.P.; Prudhomme, J.; Roch, K.L.; Fairchild, C.R.; Franzblau, S.G.; Aalbersberg, W.; Hay, M.E.; Kubanek, J. Unusual antimalarial meroditerpenes from tropical red macroalgae. Bioorg. Med. Chem. Lett. 2010, 20, 5662–5665, doi:10.1016/j.bmcl.2010.08.031.
[28]
Lin, A.S.; Stout, E.P.; Prudhomme, J.; Le Roch, K.; Fairchild, C.R.; Franzblau, S.G.; Aalbersberg, W.; Hay, M.E.; Kubanek, J. Bioactive bromophycolides R-U from the Fijian red alga Callophycus serratus. J. Nat. Prod. 2010, 73, 275–278, doi:10.1021/np900686w.
[29]
Afolayan, A.F.; Bolton, J.J.; Lategan, C.A.; Smith, P.J.; Beukes, D.R. ucoxanthin, tetraprenylated toluquinone and toluhydroquinone metabolites from Sargassum heterophyllum inhibit the in vitro growth of the malaria parasite Plasmodium falciparum. Z. Naturforsch. C. 2008, 63, 848–852.
[30]
Adams, Y.; Smith, S.L.; Schwartz-Albiez, R.; Andrews, K.T. Carrageenans inhibit the in vitro growth of Plasmodium falciparum and cytoadhesion to CD36. Parasitol Res. 2005, 97, 290–294, doi:10.1007/s00436-005-1426-3.
[31]
Chen, J.H.; Lim, J.D.; Sohn, E.H.; Choi, Y.S.; Han, E.T. Growth-inhibitory effect of a fucoidan from brown seaweed Undaria pinnatifida on Plasmodium parasites. Parasitol. Res. 2009, 104, 245–250, doi:10.1007/s00436-008-1182-2.
[32]
Pancake, S.J.; Holt, G.D.; Mellouk, S.; Hoffman, S.L. Malaria sporozoites and circums-porozoite proteins bind specifically to sulfated glycoconjugates. J. Cell Biol. 1992, 117, 1351–1357, doi:10.1083/jcb.117.6.1351.
[33]
Hanson, K.K.; Ressurrei？ao, A.S.; Buchholz, K.; Prudencio, M.; Herman-Ornelas, J.D.; Rebelo, M.; Beatty, W.L.; Wirth, D.F.; H？nscheid, T.; Moreira, R.; et al. Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins. Proc. Natl. Acad. Sci. USA 2013, 110, E2838–E2847, doi:10.1073/pnas.1306097110.
[34]
Waller, R.F.; Keeling, P.J.; Donald, R.G.; Striepen, B.; Handman, E.; Lang-Unnasch, N.; Cowman, A.F.; Besra, G.S.; Roos, D.S.; McFadden, G.I. Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 1998, 95, 12352–12357, doi:10.1073/pnas.95.21.12352.
[35]
Janouskovec, J.; Horak, A.; Obornik, M.; Lukes, J.; Keeling, P.J. A common red algal origin of the apicomplexan, dinoflagellate, and heterokont plastids. Proc. Natl. Acad. Sci. USA 2010, 107, 10949–10954, doi:10.1073/pnas.1003335107.
[36]
Baschong, W.; Wittlin, S.; Inglis, K.A.; Fairlamb, A.H.; Croft, S.L.; Kumar, T.R.; Fidock, D.A.; Brun, R. Triclosan is minimally effective in rodent malaria models. Nat. Med. 2011, 17, 33–34, doi:10.1038/nm0111-33.
[37]
Singh, A.P.; Surolia, N.; Surolia, A. Triclosan inhibit the growth of the late liver-stage of Plasmodium. IUBMB Life 2009, 61, 923–928, doi:10.1002/iub.237.
Huber, W.; Koella, J.C. A comparison of the three methods of estimating EC50 in studies of drug resistance of malaria parasites. Acta Trop. 1993, 55, 257–261, doi:10.1016/0001-706X(93)90083-N.
[40]
Ploemen, I.H; Prudencio, M.; Douradinha, B.G.; Ramesar, J.; Fonager, J.; van Gemert, G.J.; Luty, A.J.; Hermsen, C.C.; Sauerwein, R.W.; Baptista, F.G.; et al. Visualisation and quantitative analysis of the rodent malaria liver stage by real time imaging. PLoS One 2009, 4, e7881, doi:10.1371/journal.pone.0007881.
[41]
Rodrigues, T.; da Cruz, F.P.; Lafuente-Monasterio, M.J.; Gon？alves, D.; Ressurrei？ao, A.S.; Sitoe, A.R.; Bronze, M.R.; Gut, J.; Schneider, G.; Mota, M.M.; et al. Quinolin-4(1H)-imines are potent antiplasmodial drugs targeting the liver stage of malaria. J. Med. Chem. 2013, 56, 4811–4815, doi:10.1021/jm400246e.
