The mechanisms of resistance to antimalarial drugs in Plasmodium falciparum
The mechanisms of resistance to antimalarial drugs in Plasmodium falciparum
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DOI：
10.1046/j.1472-8206.2003.00164.x
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发表时间：
2003-04-01
影响因子：
2.9
通讯作者：
Durand, R
中科院分区：
文献类型：
--
作者：
Le Bras, J;Durand, R
抗药性疟疾主要是由恶性疟原虫引起的，这是一种在热带非洲、亚马逊地区和东南亚高度流行的物种。它会引起严重的发烧或贫血，每年导致100多万人死亡。氯喹抗药性的出现与某些流行地区居民中疟疾死亡率的急剧增加有关。随着对耐受性良好的药物产生多重耐药性，化学预防的理由正在减弱。恶性疟原虫抗药性疟疾起源于染色体突变。分子分析。遗传学和生物化学方法已经表明：（i）寄生虫空泡对氯喹的摄取受损是抗性菌株的共同特征，并且这种表型与Pfmdr 1、Pfcg 2和Pfcrt基因的突变相关;（ii）抗叶酸剂的酶靶二氢叶酸还原酶（DHFR）的1 - 4个点突变（乙胺嘧啶和氯胍）对这些药物产生中度至高度的耐药性：（iii）对磺胺类和砜类的耐药性机制涉及二氢蝶酸合酶（DHPS）的突变，其酶靶点：（iv）用磺胺嘧啶-乙胺嘧啶处理选择DHFR变体Ile（51）、Arg（59）和Asn（108）以及DHPS变体Ser（436）、Gly（437）和Glu（540）：㈤对某些传统抗疟剂具有抗药性的克隆体对新的抗疟剂产生抗药性的频率很高（加速耐药多药，ARMD）。氨基醇类药物（奎宁、甲氟喹和卤泛群）的耐药机制尚不清楚。流行病学研究已经确定，氯喹耐药突变体的频率在孤立的寄生虫种群中各不相同，而对抗叶酸剂的耐药性在大多数疟疾流行国家非常普遍。确定和强大的药物压力加上抗寄生虫免疫力低，可能解释了东南亚和南美洲森林中遇到的多重抗药性。在非洲，疟原虫频繁的基因重组源于疟疾的高度传播，恶性疟原虫对氯喹的抗药性流行率似乎稳定在与对氯喹敏感的疟疾相同的水平。然而，阻力水平可能因地点和时间而异。体内和体外试验未提供足够准确的耐药性图谱。迫切需要低成本的生物化学工具来进行抗性的前瞻性监测。
Drug-resistant malaria is primarily caused by Plasmodium falciparum, a species highly prevalent in tropical Africa, the Amazon region and South-east Asia. It causes severe fever or anaemia that leads to more than a million deaths each year. The emergence of chloroquine resistance has been associated with a dramatic increase in malaria mortality among inhabitants of some endemic regions. The rationale for chemoprophylaxis is weakening as multiple-drug resistance develops against well-tolerated drugs. Plasmodium falciparum drug-resistant malaria originates from chromosome mutations. Analysis by molecular. genetic and biochemical approaches has shown that (i) impaired chloroquine uptake by the parasite vacuole is a common characteristic of resistant strains, and this phenotype is correlated with mutations of the Pfmdr1, Pfcg2 and Pfcrt genes; (ii) one to four point mutations of dihydrofolate reductase (DHFR), the enzyme target of antifolates (pyrimethamine and proguanil) produce a moderate to high level of resistance to these drugs: (iii) the mechanism of resistance to sulfonamides and sulfones involves mutations of dihydropteroate synthase (DHPS), their enzyme target: (iv) treatment with sulphadoxine-pyrimethamine selects for DHFR variants Ile(51), Arg(59), and Asn(108) and for DHPS variants Ser(436), Gly(437), and Glu(540): (v) clones that were resistant to some traditional antimalarial agents acquire resistance to new ones at a high frequency (accelerated resistance to multiple drugs, ARMD). The mechanisms of resistance for amino-alcohols (quinine, mefloquine and halofantrine) are still unclear. Epidemiological studies have established that the frequency of chloroquine resistant mutants varies among isolated parasite populations, while resistance to antifolates is highly prevalent in most malarial endemic countries. Established and strong drug pressure combined with low antiparasitic immunity probably explains the multidrug-resistance encountered in the forests of South-east Asia and South America. In Africa, frequent genetic recombinations in Plasmodium originate from a high level of malaria transmission, and falciparum chloroquine-resistant prevalence seems to stabilize at the same level as chloroquine-sensitive malaria. Nevertheless, resistance levels may differ according to place and time. In vivo and in vitro tests do not provide an adequate accurate map of resistance. Biochemical tools at a low cost are urgently needed for prospective monitoring of resistance.