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J. Biol. Chem., Vol. 279, Issue 37, 38260-38266, September 10, 2004

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Resistance of Entamoeba histolytica to the Cysteine Proteinase Inhibitor E64 Is Associated with Secretion of Pro-enzymes and Reduced Pathogenicity^*

Nicolas Nowak, Hannelore Lotter, Egbert Tannich, and Iris Bruchhaus

From the Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany

Cysteine proteinases (CPs) have been considered suitable targets for the development of antiparasitic drugs. To assess the importance of CPs for the growth and pathogenicity of the protozoan parasite Entamoeba histolytica we have cultured amoebae in the presence of various cysteine proteinase inhibitors (CPIs). It was found that broad range CPIs, which are membrane permeable and rapidly enter the cell, are highly toxic at micromolar concentrations, and all attempts to generate E. histolytica mutants resistant to these CPIs were unsuccessful. In contrast, the broad range CPI E64, which does not permeate membranes as well, was deleterious at much higher concentrations, and amoebae rapidly developed resistance to this inhibitor. Compared with sensitive wild-type cells, E64-resistant E. histolytica were substantially reduced in the expression of various CP genes and were able to secrete unprocessed enzyme into the culture medium. Moreover, E64 resistance was associated with a significant reduction in virulence, because these cells were greatly impaired in the ability to generate liver abscesses in experimentally infected gerbils.

Received for publication, May 12, 2004 , and in revised form, June 21, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft (Br 1744/1-5). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Submitted in partial fulfillment of the requirements for a Ph.D. (Faculty of Biology, University of Hamburg, Hamburg, Germany).

To whom correspondence should be addressed: Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, 20359 Hamburg, Germany. Tel.: 49-4042818472; Fax: 49-4042818512; E-mail: bruchhaus{at}bni-hamburg.de.

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