Le Bras J, Basco L K, de Pécoulas P E
Centre National de Référence de la Chimiosensibilité du Paludisme, Hôpital Bichat-Claude-Bernard, Paris.
C R Seances Soc Biol Fil. 1996;190(4):471-85.
Drug resistant malaria is mostly due to Plasmodium falciparum, a species highly prevalent in tropical Africa, Amazonia and South-East Asia and responsible for severe involvement of fever or anemia prompting more than a million death per year. Resistance originate from chromosomic mutations. Antimetabolite-resistant mutants (pyrimethamine and proguanil) are highly prevalent in Asia, America and East Africa. One to 3 point mutations on the dihydrofolate-reductase gene, the target enzyme, give moderate to high level of resistance. Molecular biology furnishes sensitive tools for population-based studies of resistance to these compounds. Four-aminoquinolines resistant mutants (chloroquine and amodiaquine) were encountered more than 10 years after a huge amount of these drugs has been sold. The level of resistance varies among parasites isolates populations. Impaired uptake of the drug by the parasite vacuole is a common characteristic of resistant strains. This phenotype is poorly correlated with PfMDR1 gene mutations on chromosome 5 but is strongly associated with a particular RFLP profile on chromosome 7. Amino-alcohol resistant falciparum malaria is scarce (quinine, mefloquine, halofantrine) and supposed to be associated with impaired uptake of the drug by the parasite, the mechanism of which is still unclear. In each of these three antimalarial drugs groups, the highly resistant level to a peticular compound, the highly prevalence of cross resistance of the malaria isolate. An established and strong drug pressure probably explains the multi-chemoresistance encoutered in South-East Asia and forests of South America. In Africa, frequent genetic recombinations in Plasmodium originates from a high level of malaria transmission, and falciparum chloroquine-resistance prevalence seems to stabilize at an equal level as chloroquine-sensitive malaria.
耐药性疟疾主要由恶性疟原虫引起，该物种在热带非洲、亚马逊地区和东南亚高度流行，每年导致超过100万人因严重发热或贫血而死亡。耐药性源于染色体突变。抗代谢物耐药突变体（乙胺嘧啶和氯胍）在亚洲、美洲和东非高度流行。二氢叶酸还原酶基因（靶酶）上的1至3个点突变产生中度至高度耐药性。分子生物学为基于人群的这些化合物耐药性研究提供了灵敏工具。在大量销售这些药物十多年后，出现了对4-氨基喹啉类药物耐药的突变体（氯喹和阿莫地喹）。不同寄生虫分离群体的耐药水平各不相同。寄生虫液泡对药物摄取受损是耐药菌株的一个共同特征。这种表型与5号染色体上的PfMDR1基因突变相关性较差，但与7号染色体上的特定限制性片段长度多态性图谱密切相关。对氨基醇耐药的恶性疟病例较少（奎宁、甲氟喹、卤泛群），推测与寄生虫对药物摄取受损有关，其机制尚不清楚。在这三类抗疟药物中，对某一种特定化合物的高度耐药水平以及疟原虫分离株交叉耐药的高流行率。既定且强大的药物压力可能解释了在东南亚和南美洲森林中遇到的多重化学耐药性。在非洲，疟原虫中频繁的基因重组源于高水平的疟疾传播，恶性疟原虫对氯喹耐药的流行率似乎稳定在与氯喹敏感疟疾相同的水平。
