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Nature Research, Scientific Reports, 1(7), 2017

DOI: 10.1038/srep40406

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Targeting pathogen metabolism without collateral damage to the host

Journal article published in 2017 by Jurgen R. Haanstra ORCID, Francois du Toit, Albert Gerding, Amalia M. Dolga, Freek J. H. Sorgdrager ORCID, Manon Buist-Homan, F. Du Toit, Klaas Nico Faber, Hermann-Georg Holzhuetter, Hermann-Georg Holzhütter, Balazs Szoor, Keith R. Matthews, Jacky L. Snoep ORCID, Hans V. Westerhoff, Barbara M. Bakker
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

AbstractThe development of drugs that can inactivate disease-causing cells (e.g. cancer cells or parasites) without causing collateral damage to healthy or to host cells is complicated by the fact that many proteins are very similar between organisms. Nevertheless, due to subtle, quantitative differences between the biochemical reaction networks of target cell and host, a drug can limit the flux of the same essential process in one organism more than in another. We identified precise criteria for this ‘network-based’ drug selectivity, which can serve as an alternative or additive to structural differences. We combined computational and experimental approaches to compare energy metabolism in the causative agent of sleeping sickness, Trypanosoma brucei, with that of human erythrocytes, and identified glucose transport and glyceraldehyde-3-phosphate dehydrogenase as the most selective antiparasitic targets. Computational predictions were validated experimentally in a novel parasite-erythrocytes co-culture system. Glucose-transport inhibitors killed trypanosomes without killing erythrocytes, neurons or liver cells.