Price R N, Cassar C, Brockman A, Duraisingh M, van Vugt M, White N J, Nosten F, Krishna S
Department of Infectious Diseases, St. George's Hospital Medical School, London, United Kingdom.
Antimicrob Agents Chemother. 1999 Dec;43(12):2943-9. doi: 10.1128/AAC.43.12.2943.
On the western border of Thailand, Plasmodium falciparum has become resistant to almost all antimalarial agents. The molecular basis of resistance in these parasite populations has not been well characterized. This study assessed genetic polymorphisms in the pfmdr1 gene in 54 parasites collected from the western border of Thailand to determine the relationship of pfmdr1 copy number and codon mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine, quinine, and artesunate assessed in vitro. A point mutation at codon 86 (resulting in a change of Asn to Tyr) was associated with a significantly lower 50% inhibitory concentration (IC(50)) of mefloquine (median, 9 ng/ml versus 52.4 ng/ml; P = 0.003). Overall 35% of the isolates (19 of 54) had an increase in pfmdr1 copy number, and all 19 carried the wild-type allele at codon 86. Increased pfmdr1 copy number was associated with higher IC(50)s of mefloquine (P = 0.04) and artesunate (P = 0.005), independent of polymorphism at codon 86. The relationship between pfmdr1 and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype.
在泰国西部边境，恶性疟原虫已对几乎所有抗疟药物产生耐药性。这些疟原虫种群耐药性的分子基础尚未得到充分表征。本研究评估了从泰国西部边境收集的54株疟原虫中pfmdr1基因的遗传多态性，以确定pfmdr1拷贝数和密码子突变与体外评估的疟原虫对甲氟喹、氯喹、卤泛群、奎宁和青蒿琥酯敏感性之间的关系。密码子86处的点突变（导致天冬酰胺变为酪氨酸）与甲氟喹的50%抑制浓度（IC50）显著降低相关（中位数，9纳克/毫升对52.4纳克/毫升；P = 0.003）。总体而言，35%的分离株（54株中的19株）pfmdr1拷贝数增加，所有19株在密码子86处携带野生型等位基因。pfmdr1拷贝数增加与甲氟喹（P = 0.04）和青蒿琥酯（P = 0.005）的较高IC50相关，与密码子86处的多态性无关。pfmdr1与对结构不同的抗疟药物的耐药性之间的关系证实了真正的多药耐药表型的存在。
