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Mutations in Cytochrome b Resulting in Atovaquone Resistance Are Associated with Loss of Fitness in Plasmodium falciparum

Malaria Laboratory, Infectious Diseases Unit, The Queensland Institute of Medical Research,¹ Parasitology Department, Australian Army Malaria Institute,² Centre for Molecular Biotechnology, Queensland University of Technology,⁴ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia,³ Malaria Vaccine Development Unit, National Institutes of Health, Bethesda, Maryland⁵

Received 8 March 2002/ Returned for modification 3 April 2002/ Accepted 1 May 2002

Drug resistance in malarial parasites has become a major obstacle in the control of the disease. Strategies are urgently needed to control the development of resistance and to possibly reverse existing resistance. One key element required to reverse malaria drug resistance is for the parasites to "pay" a biological "cost" or suffer a loss of fitness when acquiring resistance to antimalarial drugs. Such a situation would be a disadvantage to the resistant parasites in the absence of drug pressure. We compared here the relative fitness of atovaquone-resistant Plasmodium falciparum K1 clones with single and double base mutations in their cytochrome b genes to their parent clones during erythrocytic stages in the absence of drug pressure. We found that the double amino acid mutation (M133I and G280D) is associated with a 5 to 9% loss of fitness and that the single amino acid change of M133I did not result in any detectable loss of fitness. Molecular modeling of the interaction of P. falciparum cytochrome b with ubiquinone led to the prediction that a loss of fitness of the malaria parasites would result from the G280D mutation due to its close proximity to the putative ubiquinone-binding site. This appears to have resulted in a weakening of the cytochrome b-ubiquinone complex, thereby causing the electron transport chain to become less efficient. Our results suggest that the prevalence of resistant parasites may decrease after the drug usage is discontinued.

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