title: Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and application of statins as a novel effective therapeutic approach against Acanthamoeba infections.
abstract: Acanthamoeba is an opportunistic pathogen in humans, whose infections most commonly manifest as Acanthamoeba keratitis or, more rarely, granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment of Acanthamoeba, they are generally lengthy and/or have limited efficacy. Therefore, there is a requirement for the identification, validation, and development of novel therapeutic targets against these pathogens. Recently, RNA interference (RNAi) has been widely used for these validation purposes and has proven to be a powerful tool for Acanthamoeba therapeutics. Ergosterol is one of the major sterols in the membrane of Acanthamoeba. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, one of the precursors for the production of cholesterol in humans and ergosterol in plants, fungi, and protozoa. Statins are compounds which inhibit this enzyme and so are promising as chemotherapeutics. In order to validate whether this enzyme could be an interesting therapeutic target in Acanthamoeba, small interfering RNAs (siRNAs) against HMG-CoA were developed and used to evaluate the effects induced by the inhibition of Acanthamoeba HMG-CoA. It was found that HMG-CoA is a potential drug target in these pathogenic free-living amoebae, and various statins were evaluated in vitro against three clinical strains of Acanthamoeba by using a colorimetric assay, showing important activities against the tested strains. We conclude that the targeting of HMG-CoA and Acanthamoeba treatment using statins is a novel powerful treatment option against Acanthamoeba species in human disease.
authors.affiliation: University Institute of Tropical Diseases and Public Health of the Canary Islands, University of La Laguna, La Laguna, Tenerife, Canary Islands, Spain. cmmartin@ull.es
authors.forename: Carmen María
authors.initials: CM
authors.lastname: Martín-Navarro
authors.forename: Jacob
authors.initials: J
authors.lastname: Lorenzo-Morales
authors.forename: Rubén P
authors.initials: RP
authors.lastname: Machin
authors.forename: Atteneri
authors.initials: A
authors.lastname: López-Arencibia
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García-Castellano
authors.forename: Isabel
authors.initials: I
authors.lastname: de Fuentes
authors.forename: Brendan
authors.initials: B
authors.lastname: Loftus
authors.forename: Sutherland K
authors.initials: SK
authors.lastname: Maciver
authors.forename: Basilio
authors.initials: B
authors.lastname: Valladares
authors.forename: José E
authors.initials: JE
authors.lastname: Piñero
mesh_terms: D048248:Acanthamoeba castellanii / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors / Q000378:metabolism; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D057075:Enzyme Assays; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000235:genetics / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008798:Mevalonic Acid / Q000378:metabolism; D008969:Molecular Sequence Data; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000214:Acyl Coenzyme A; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015800:Protozoan Proteins; D034741:RNA, Small Interfering; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D008798:Mevalonic Acid