Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum

Peters, JM, Chen, NH, Gatton, M, Korsinczky, M, Fowler, EV, Manzetti, S, Saul, A and Cheng, Q (2002) Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum. Antimicrobial Agents And Chemotherapy, 46 8: 2435-2441. doi:10.1128/AAC.46.8.2435-2441.2002

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Author Peters, JM
Chen, NH
Gatton, M
Korsinczky, M
Fowler, EV
Manzetti, S
Saul, A
Cheng, Q
Title Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum
Journal name Antimicrobial Agents And Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
Publication date 2002
Sub-type Article (original research)
DOI 10.1128/AAC.46.8.2435-2441.2002
Open Access Status File (Publisher version)
Volume 46
Issue 8
Start page 2435
End page 2441
Total pages 7
Place of publication Washington
Publisher Amer Soc Microbiology
Language eng
Abstract 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.
Keyword Microbiology
Pharmacology & Pharmacy
Molecular-dynamics
Pyrimethamine Resistance
Malaria Parasites
Bc(1) Complex
In-vivo
Chloroquine
Drug
Infections
Diversity
Advantage
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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Created: Wed, 17 Oct 2007, 10:44:56 EST