title: Artemether Exhibits Amoebicidal Activity against Acanthamoeba castellanii through Inhibition of the Serine Biosynthesis Pathway.
abstract: Acanthamoeba sp. parasites are the causative agents of Acanthamoeba keratitis, fatal granulomatous amoebic encephalitis, and cutaneous infections. However, there are currently no effective drugs for these organisms. Here, we evaluated the activity of the antimalarial agent artemether against Acanthamoeba castellanii trophozoites and identified potential targets of this agent through a proteomic approach. Artemether exhibited in vitro amoebicidal activity in a time- and dose-dependent manner and induced ultrastructural modification and cell apoptosis. The iTRAQ quantitative proteomic analysis identified 707 proteins that were differentially expressed after artemether treatment. We focused on phosphoglycerate dehydrogenase and phosphoserine aminotransferase in the serine biosynthesis pathway because of their importance to the growth and proliferation of protozoan and cancer cells. The expression of these proteins in Acanthamoeba was validated using quantitative real-time PCR and Western blotting after artemether treatment. The changes in the expression levels of phosphoserine aminotransferase were consistent with those of phosphoglycerate dehydrogenase. Therefore, the downregulation of phosphoserine aminotransferase may be due to the downregulation of phosphoglycerate dehydrogenase. Furthermore, exogenous serine might antagonize the activity of artemether against Acanthamoeba trophozoites. These results indicate that the serine biosynthesis pathway is important to amoeba survival and that targeting these enzymes would improve the treatment of Acanthamoeba infections. Artemether may be used as a phosphoglycerate dehydrogenase inhibitor to control or block Acanthamoeba infections.
authors.affiliation: Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ran
authors.affiliation: Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Suqin
authors.initials: S
authors.lastname: Man
authors.affiliation: Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Electron Microscopy, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Gao
authors.affiliation: ACEA Bio (Hangzhou) Co., Ltd., Hangzhou, Zhejiang Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Infectious Diseases, Tokai University School of Medicine, Isehara, Kanagawa, Japan htachiba@is.icc.u-tokai.ac.jp xjcheng@shmu.edu.cn.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tachibana
authors.affiliation: Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai, China htachiba@is.icc.u-tokai.ac.jp xjcheng@shmu.edu.cn.
authors.forename: Xunjia
authors.initials: X
authors.lastname: Cheng
mesh_terms: D015823:Acanthamoeba Keratitis / Q000188:drug therapy / Q000378:metabolism / Q000469:parasitology; D048248:Acanthamoeba castellanii / Q000187:drug effects* / Q000378:metabolism; D000562:Amebiasis / Q000188:drug therapy / Q000378:metabolism / Q000469:parasitology; D000563:Amebicides / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077549:Artemether; D037621:Artemisinins / Q000494:pharmacology*; D053898:Biosynthetic Pathways / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism / Q000469:parasitology; D050543:Phosphoglycerate Dehydrogenase / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D012694:Serine / Q000378:metabolism*; D000637:Transaminases / Q000378:metabolism; D053058:Trophozoites / Q000469:parasitology
chemical_list: D000563:Amebicides; D000962:Antimalarials; D037621:Artemisinins; D012694:Serine; D000077549:Artemether; D050543:Phosphoglycerate Dehydrogenase; D000637:Transaminases; C022393:phosphoserine aminotransferase