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

doi:10.1128/AAC.44.8.2100-2108.2000

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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 malariaparasites become resistant to atovaquone quickly if atovaquoneis used as a sole agent. The mechanism by which the parasite developsresistance to atovaquone is not yet fully understood. Atovaquonehas been shown to inhibit the cytochrome bc₁ (CYT bc₁) complexof the electron transport chain of malaria parasites. Here wereport point mutations in Plasmodium falciparum CYT b that areassociated with atovaquone resistance. Single or double aminoacid mutations were detected from parasites that originated froma cloned line and survived various concentrations of atovaquonein vitro. A single amino acid mutation was detected in parasitesisolated from a recrudescent patient following atovaquone treatment.These mutations are associated with a 25- to 9,354-fold rangereduction in parasite susceptibility to atovaquone. Molecularmodeling showed that amino acid mutations associated with atovaquoneresistance are clustered around a putative atovaquone-bindingsite. Mutations in these positions are consistent with a reducedbinding 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.

Published with the permission of the Director General of Army HealthServices.

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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