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

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 “p...

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সংরক্ষণ করুন:
গ্রন্থ-পঞ্জীর বিবরন
প্রধান লেখক: Peters, Jennifer M., Chen, Nanhua, Gatton, Michelle, Korsinczky, Michael, Fowler, Elizabeth V., Manzetti, Sergio, Saul, Allan, Cheng, Qin
বিন্যাস: প্রবন্ধ
ভাষা:en
প্রকাশিত: American Society for Microbiology 2002
বিষয়গুলি:
Mechanisms of Resistance
অনলাইন ব্যবহার করুন:https://ncbi.nlm.nih.gov/pmc/articles/PMC127342/
https://ncbi.nlm.nih.gov/pubmed/12121915
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1128/AAC.46.8.2435-2441.2002
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id pubmed-127342
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spelling pubmed-1273422003-04-01 Mutations in Cytochrome b Resulting in Atovaquone Resistance Are Associated with Loss of Fitness in Plasmodium falciparum Peters, Jennifer M. Chen, Nanhua Gatton, Michelle Korsinczky, Michael Fowler, Elizabeth V. Manzetti, Sergio Saul, Allan Cheng, Qin Antimicrob Agents Chemother Mechanisms of Resistance 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. American Society for Microbiology 2002-08 /pmc/articles/PMC127342/ /pubmed/12121915 http://dx.doi.org/10.1128/AAC.46.8.2435-2441.2002 Text en Copyright © 2002, American Society for Microbiology
institution US National Library of Medicine
collection PubMed Central
language en
format Article
topic Mechanisms of Resistance
spellingShingle Mechanisms of Resistance
Peters, Jennifer M.
Chen, Nanhua
Gatton, Michelle
Korsinczky, Michael
Fowler, Elizabeth V.
Manzetti, Sergio
Saul, Allan
Cheng, Qin
Mutations in Cytochrome b Resulting in Atovaquone Resistance Are Associated with Loss of Fitness in Plasmodium falciparum
description 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.
author Peters, Jennifer M.
Chen, Nanhua
Gatton, Michelle
Korsinczky, Michael
Fowler, Elizabeth V.
Manzetti, Sergio
Saul, Allan
Cheng, Qin
author_facet Peters, Jennifer M.
Chen, Nanhua
Gatton, Michelle
Korsinczky, Michael
Fowler, Elizabeth V.
Manzetti, Sergio
Saul, Allan
Cheng, Qin
author_sort Peters, Jennifer M.
title Mutations in Cytochrome b Resulting in Atovaquone Resistance Are Associated with Loss of Fitness in Plasmodium falciparum
title_short Mutations in Cytochrome b Resulting in Atovaquone Resistance Are Associated with Loss of Fitness in Plasmodium falciparum
title_full Mutations in Cytochrome b Resulting in Atovaquone Resistance Are Associated with Loss of Fitness in Plasmodium falciparum
title_fullStr Mutations in Cytochrome b Resulting in Atovaquone Resistance Are Associated with Loss of Fitness in Plasmodium falciparum
title_full_unstemmed Mutations in Cytochrome b Resulting in Atovaquone Resistance Are Associated with Loss of Fitness in Plasmodium falciparum
title_sort mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in plasmodium falciparum
publisher American Society for Microbiology
publisher_facet American Society for Microbiology
publishDate 2002
url https://ncbi.nlm.nih.gov/pmc/articles/PMC127342/
https://ncbi.nlm.nih.gov/pubmed/12121915
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1128/AAC.46.8.2435-2441.2002
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