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Antimicrobial Agents and Chemotherapy, August 2000, p. 2100-2108, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mutations in Plasmodium falciparum Cytochrome b That Are Associated with Atovaquone Resistance Are Located at a Putative Drug-Binding Site†

Michael Korsinczky,1,2 Nanhua Chen,1 Barbara Kotecka,1 Allan Saul,3 Karl Rieckmann,1 and Qin Cheng1,*

Parasitology and Arbovirology Department, Australian Army Malaria Institute,1 Institute for Molecular Bioscience, University of Queensland, St. Lucia,2 and Malaria and Arbovirus Unit, The Queensland Institute of Medical Research,3 Brisbane, Australia

Received 10 January 2000/Returned for modification 6 March 2000/Accepted 14 April 2000

Atovaquone is the major active component of the new antimalarial drug Malarone. Considerable evidence suggests that malaria parasites become resistant to atovaquone quickly if atovaquone is used as a sole agent. The mechanism by which the parasite develops resistance to atovaquone is not yet fully understood. Atovaquone has been shown to inhibit the cytochrome bc1 (CYT bc1) complex of the electron transport chain of malaria parasites. Here we report point mutations in Plasmodium falciparum CYT b that are associated with atovaquone resistance. Single or double amino acid mutations were detected from parasites that originated from a cloned line and survived various concentrations of atovaquone in vitro. A single amino acid mutation was detected in parasites isolated from a recrudescent patient following atovaquone treatment. These mutations are associated with a 25- to 9,354-fold range reduction in parasite susceptibility to atovaquone. Molecular modeling showed that amino acid mutations associated with atovaquone resistance are clustered around a putative atovaquone-binding site. Mutations in these positions are consistent with a reduced binding affinity of atovaquone for malaria parasite CYT b.

* Corresponding author. Mailing address: Australian Army Malaria Institute, Gallipoli Barracks, Enoggera, Queensland 4052, Australia. Phone: 61-7-33324834. Fax: 61-7-33324800. E-mail: qin.cheng{at}defence.gov.au.

dagger Published with the permission of the Director General of Army Health Services.

Antimicrobial Agents and Chemotherapy, August 2000, p. 2100-2108, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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