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Antimicrob. Agents Chemother. doi:10.1128/AAC.00423-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Antiproliferative effect of dihydroxyacetone on Trypanosoma brucei bloodstream forms: Cell cycle progression, subcellular alterations and cell death

Interfaculty Institute of Biochemistry, University of Tuebingen, Germany, Institute of Physiology, University of Tuebingen, Germany

^* To whom correspondence should be addressed. Email: uzcategn{at}ucv.ve. michael.duszenko{at}uni-tuebingen.de.

	Abstract

We evaluated the effects of dihydroxyacetone (DHA) on Trypanosoma brucei bloodstream forms. DHA is considered an energy source for many different cell types. T. brucei takes up DHA readily due to the presence of aquaglyceroporins. However, the parasite is unable to use it as a carbon source because of the absence of dihydroxyacetone kinase (DHAK): We could not find a homolog of the respective gene in the genomic data base of this parasite, have been unable to detect a DHAK activity in cell lysates of T. brucei and the parasite died quickly if DHA was the sole energy source in the media. In addition, during trypanosome cultivation DHA induced a growth inhibition with an IC₅₀ of about 1 mM, a concentration which is completely innocuous to mammals. Here DHA caused a cell cycle arrest in the G2/M phase of up to 70% at a concentration of 2 mM DHA. Also, DHA-treated parasites showed profound ultrastructural alterations including an increase of vesicular structures within the cytosol, the presence of multivesicular bodies, myelin-like structures and autophagy-like vacuoles as well as a marked disorder of the characteristic mitochondrion structure. Based on the toxicity of DHA for trypanosomes compared with mammals, we consider DHA as a starting point for a rational drug design of new trypanocidal drugs.