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Antimicrobial Agents and Chemotherapy, February 2007, p. 667-672, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.01064-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mechanism of Antimalarial Action of the Synthetic Trioxolane RBX11160 (OZ277){triangledown}

Anne-Catrin Uhlemann,1 Sergio Wittlin,2 Hugues Matile,3 Leyla Y. Bustamante,1 and Sanjeev Krishna1*

Division of Cellular and Molecular Medicine, Centre for Infection, St. George's University of London, Cranmer Terrace, London SW17 0RE, Great Britain,1 Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland,2 F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland3

Received 23 August 2006/ Returned for modification 26 October 2006/ Accepted 20 November 2006

RBX11160 (OZ277) is a fully synthetic peroxidic antimalarial in clinical development. To study the possible mechanisms of action of RBX11160, we have examined its ability to inhibit PfATP6, a sarcoplasmic reticulum calcium ATPase and proposed target for semisynthetic peroxidic artemisinin derivatives. RBX11160 inhibits PfATP6 (apparent half-maximal inhibitory constant = 7,700 nM) less potently than artemisinin (79 nM). Inhibition of PfATP6 is abrogated by desferrioxamine, an iron-chelating agent. Consistent with this finding, the killing of Plasmodium falciparum organisms by RBX11160 in vitro is antagonized by desferrioxamine. Artesunate and RBX11160 also act antagonistically against P. falciparum in vitro. A fluorescent derivative of RBX11160 localizes to the parasite cytosol in some parasites and to the food vacuole in other parasites. These data demonstrate that there are both similarities and differences between the antimalarial properties of RBX11160 and those of semisynthetic antimalarials such as artesunate and artemisinin.

* Corresponding author. Mailing address: Dept. of Infectious Diseases, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, United Kingdom. Phone: 44 208 725 5836. Fax: 44 208 725 3487. E-mail: s.krishna{at}sgul.ac.uk.

{triangledown} Published ahead of print on 4 December 2006.

Antimicrobial Agents and Chemotherapy, February 2007, p. 667-672, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.01064-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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