Potential of Lichen Secondary Metabolites against Plasmodium Liver Stage Parasites with FAS-II as the Potential Target


Lauinger, IL; Vivas, L; Perozzo, R; Stairiker, C; Tarun, A; Zloh, M; Zhang, XJ; Xu, H; Tonge, PJ; Franzblau, SG; Pham, DH; Esguerra, CV; Crawford, AD; Maes, L; Tasdemir, D; (2013) Potential of Lichen Secondary Metabolites against Plasmodium Liver Stage Parasites with FAS-II as the Potential Target. Journal of natural products, 76 (6). pp. 1064-1070. ISSN 0163-3864 DOI: https://doi.org/10.1021/np400083k

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Abstract

Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1); vulpic acid (2), psoromic acid (3), and, (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition Of P. falciparum blood Stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC50 value 2.3 mu M, BS IC50 value 47.3 mu M). The compounds 1 - 3 inhibited one Or more enzymes (Pf FabI, PfFabG, and pfFabZ), from the Plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug. target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1-4 were also evaluated against FabI homologues and Whole cells of various pathogens -(S. aureus, E. coli M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential. toxicity, of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo):. This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents.

Item Type: Article
Keywords: fatty-acid biosynthesis, carrier protein reductase, enoyl-acp reductase, usnic acid, in-vitro, antimycobacterial activity, staphylococcus-aureus, antimalarial activity, drug discovery, falciparum
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Malaria Centre
PubMed ID: 23806111
Web of Science ID: 321320600011
URI: http://researchonline.lshtm.ac.uk/id/eprint/1229441

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