Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full text: (LINK). Abstract, edited.]
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INHIBITION OF HMG-CoA REDUCTASE AND THE APPLICATION OF STATINS AS A NOVEL EFFECTIVE THERAPEUTIC APPROACH AGAINST ACANTHAMOEBA INFECTIONS.
Carmen Mar?a Mart?n-Navarro 1,*, Jacob Lorenzo-Morales 1, Rub?n P. Machin 2, Atteneri L?pez-Arencibia 1, Jos? Manuel Garc?a-Castellano 2, Isabel de Fuentes 3, Brendan Loftus 4, Sutherland K. Maciver 5, Basilio Valladares 1 and Jos? E. Pi?ero 1
Author Affiliations: <SUP>1</SUP>University Institute of Tropical Diseases and Public Health of the Canary Islands, University of La Laguna, Avda Astrof?sico Fco. S?nchez, S/N, 38203 La Laguna, Tenerife, Canary Islands, Spain; <SUP>2</SUP>Molecular Oncology Group (G-OncoMol). Research Unit. University Hospital of Gran Canaria Dr. Negr?n. Barranco La Ballena. 35020 Las Palmas de Gran Canaria. Canary Islands. Spain; <SUP>3</SUP>Carlos III Health Institute. Microbiology National Center. Ctra. Majadahonda-Pozuelo Km 2, 28220 Majadahonda, Madrid, Spain; <SUP>4</SUP>School of Medicine and Medical Science, Conway Institute. University College Dublin. Belfield. Dublin 4, Ireland; <SUP>5</SUP>Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh. Hugh Robson Building, George Square. Edinburgh EH8 9XD. Scotland, United Kingdom
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, RNAi has been widely used for these validation purposes and has been previously 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 catalyses 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, siRNAs against HMG-CoA were developed and used to evaluate the effects induced by 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 using a colorimetric assay showing important activities against the tested strains. We conclude that, targeting of HMG-CoA and Acanthamoeba treatment using statins is a novel powerful treatment option against Acanthamoeba species in human disease.
FOOTNOTES
* Corresponding author: Carmen Mar?a Mart?n Navarro, Email: cmmartin@ull.es, Telephone: +34 922316502 (ext. 6111), Fax: +34 922318490
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
-Author Affiliations: <SUP>1</SUP>University Institute of Tropical Diseases and Public Health of the Canary Islands, University of La Laguna, Avda Astrof?sico Fco. S?nchez, S/N, 38203 La Laguna, Tenerife, Canary Islands, Spain; <SUP>2</SUP>Molecular Oncology Group (G-OncoMol). Research Unit. University Hospital of Gran Canaria Dr. Negr?n. Barranco La Ballena. 35020 Las Palmas de Gran Canaria. Canary Islands. Spain; <SUP>3</SUP>Carlos III Health Institute. Microbiology National Center. Ctra. Majadahonda-Pozuelo Km 2, 28220 Majadahonda, Madrid, Spain; <SUP>4</SUP>School of Medicine and Medical Science, Conway Institute. University College Dublin. Belfield. Dublin 4, Ireland; <SUP>5</SUP>Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh. Hugh Robson Building, George Square. Edinburgh EH8 9XD. Scotland, United Kingdom
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, RNAi has been widely used for these validation purposes and has been previously 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 catalyses 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, siRNAs against HMG-CoA were developed and used to evaluate the effects induced by 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 using a colorimetric assay showing important activities against the tested strains. We conclude that, targeting of HMG-CoA and Acanthamoeba treatment using statins is a novel powerful treatment option against Acanthamoeba species in human disease.
FOOTNOTES
* Corresponding author: Carmen Mar?a Mart?n Navarro, Email: cmmartin@ull.es, Telephone: +34 922316502 (ext. 6111), Fax: +34 922318490
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
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