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Antimicrobial Agents and Chemotherapy, August 2000, p. 2100-2108, Vol. 44, No. 8
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.
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
*
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 Health Services.
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