Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and application of statins as a novel effective therapeutic approach against Acanthamoeba infections.

Antimicrob Agents Chemother. 2013 Jan;57(1):375-81.

Martín-Navarro CM, Lorenzo-Morales J, Machin RP, López-Arencibia A, García-Castellano JM, de Fuentes I, Loftus B, Maciver SK, Valladares B, Piñero JE.

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

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.

PMID: 23114753

 

Supplement:

3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is an enzyme involved in the conversion of HMG-CoA to mevalonate, a precursor of cholesterol in humans and ergosterol in plants, fungi, and protozoa (Figure 1). In Acanthamoeba, ergosterol and 7-dehyrostigmasterol have been reported to be the main sterols of the membrane in both the trophozoite and the cyst forms. Therefore, if this enzyme is blocked or inhibited, defective membrane architecture, increase of permeability and leakage of ions from the cell should be expected. Statins are a group of molecules used in human for controlling cholesterol levels in order to treat hypercholesterolemia. They act by inhibiting the HMG-CoA reductase.

Carmen Mª Martín Navarro-1

Fig. 1. Ergosterol biosynthesis pathway.

In this work, the presence of this enzyme in Acanthamoeba has been demonstrated and the efficacy of three statins against Acanthamoeba strains was confirmed. It was observed that the trophozoite was inhibited by three molecules (Atorvastatin, fluvastatina, simvastatin) with an IC50 ranging from 9 to 58 mM. It is therefore possible that the present treatment for controlling cholesterol levels in patients will be suitable as a treatment for systemic infections caused by Acanthamoeba. Although, in the case of Acanthamoeba keratitis, the application of statins as an eye drops may be a better form to deliver statins.

Carmen Mª Martín Navarro-2

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