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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum.
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Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in Plasmodium falciparum.

机译：细胞色素b的突变导致对阿托奎酮的耐药性与恶性疟原虫的适应性丧失有关。

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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.
机译：疟原虫的耐药性已成为控制该疾病的主要障碍。迫切需要采取策略来控制抵抗力量的发展，并可能扭转现有的抵抗力量。逆转疟疾耐药性所需的一个关键要素是使寄生虫在获得对疟疾药物的耐药性时“付出”生物学“代价”或遭受不适。在没有药物压力的情况下，这种情况对于抗药性寄生虫将是不利的。我们在这里比较了在没有药物压力的情况下，在红细胞形成阶段，在细胞色素b基因中具有单碱基和双碱基突变的耐Atovaquone的恶性疟原虫K1克隆相对于其亲本的相对适应性。我们发现双氨基酸突变（M133I和G280D）与5％至9％的适应性降低有关，并且M133I的单个氨基酸变化并未导致任何可检测到的适应性降低。恶性疟原虫细胞色素b与泛醌相互作用的分子模型导致了以下预测：由于G280D突变与假定的泛醌结合位点非常接近，因此会导致疟原虫的适应性丧失。这似乎导致细胞色素b-泛醌复合物的减弱，从而导致电子传输链的效率降低。我们的结果表明，停用药物后耐药性寄生虫的患病率可能会降低。

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