Inhibition of 3-Hydroxy-3-Methylglutaryl–Coenzyme A Reductase and Application of Statins as a Novel Effective Therapeutic Approach against Acanthamoeba Infections

Abstract

ABSTRACTAcanthamoebais an opportunistic pathogen in humans, whose infections most commonly manifest asAcanthamoebakeratitis or, more rarely, granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment ofAcanthamoeba, 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 forAcanthamoebatherapeutics. Ergosterol is one of the major sterols in the membrane ofAcanthamoeba. 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 inAcanthamoeba, small interfering RNAs (siRNAs) against HMG-CoA were developed and used to evaluate the effects induced by the inhibition ofAcanthamoebaHMG-CoA. It was found that HMG-CoA is a potential drug target in these pathogenic free-living amoebae, and various statins were evaluatedin vitroagainst three clinical strains ofAcanthamoebaby using a colorimetric assay, showing important activities against the tested strains. We conclude that the targeting of HMG-CoA andAcanthamoebatreatment using statins is a novel powerful treatment option againstAcanthamoebaspecies in human disease.