Potential of Lichen Secondary Metabolites against Plasmodium Liver Stage Parasites with FAS-II as the Potential Target
- Authors
- Lauinger, I.L., Vivas, L., Perozzo, R., Stairiker, C., Tarun, A., Zloh, M., Zhang, X., Xu, H., Tonge, P.J., Franzblau, S.G., Pham, D.H., Esguerra, C.V., Crawford, A.D., Maes, L., and Tasdemir, D.
- ID
- ZDB-PUB-130710-92
- Date
- 2013
- Source
- Journal of natural products 76(6): 1064-1070 (Journal)
- Registered Authors
- Crawford, Alexander, Esguerra, Camila V.
- Keywords
- none
- MeSH Terms
-
- Animals
- Antimalarials/blood
- Antimalarials/chemistry
- Antimalarials/pharmacology*
- Disease Models, Animal
- Enzyme Inhibitors/blood
- Enzyme Inhibitors/chemistry
- Enzyme Inhibitors/pharmacology*
- Fatty Acid Synthase, Type II/antagonists & inhibitors*
- Fatty Acid Synthase, Type II/blood
- Hepatocytes/drug effects
- Humans
- Lichens/chemistry*
- Liver/parasitology*
- Malaria/drug therapy
- Molecular Structure
- Mycobacterium tuberculosis/drug effects
- Plasmodium berghei/drug effects
- Plasmodium falciparum/drug effects*
- Plasmodium falciparum/enzymology
- Protozoan Proteins/blood
- Protozoan Proteins/pharmacology
- Staphylococcus aureus/drug effects
- Zebrafish
- PubMed
- 23806111 Full text @ J. Nat. Prod.
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 µM, BS IC50 value 47.3 µM). The compounds 1–3 inhibited one or more enzymes (PfFabI, 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.