Associations between Varied Susceptibilities to PfATP4 Inhibitors and Genotypes in Ugandan Plasmodium falciparum Isolates.
Associations between Varied Susceptibilities to PfATP4 Inhibitors and Genotypes in Ugandan Plasmodium falciparum Isolates.
复制标题
乌干达恶性疟原虫分离株对 PfATP4 抑制剂的不同敏感性与基因型之间的关联。
DOI：
10.1128/aac.00771-21
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发表时间：
2021
影响因子：
4.9
通讯作者：
Bailey,Jeffrey
中科院分区：
文献类型：
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作者：
Kreutzfeld,Oriana;Rasmussen,StephanieA;Ramanathan,AartiA;Tumwebaze,PatrickK;Byaruhanga,Oswald;Katairo,Thomas;Asua,Victor;Okitwi,Martin;Orena,Stephen;Legac,Jennifer;Conrad,MelissaD;Nsobya,SamuelL;Aydemir,Ozkan;Bailey,Jeffrey
在最近研究的作为潜在的新抗疟疾药物的新化合物中，有三种独立开发的恶性疟原虫P型ATP酶（PfATP 4）抑制剂：KAE 609（cipargamin）、PA 92和SJ 733。我们评估了2016年至2019年在乌干达Tororo和Busia地区收集的374株新鲜恶性疟原虫分离株对这些化合物的生物活性。SJ 733、PA 92和KAE 609的中位IC 50分别为65 nM、9.1 nM和0.5 nM。其中218株pfatp 4基因的测序显示出许多非同义的单核苷酸多态性;最常见的突变是G1128 R（69%的混合或突变株）、Q1081 K/R（68%）、G223 S（25%）、N1045 K（16%）和D1116 G/N/Y（16%）。G223 S突变与SJ 733、PA 92和KAE 609的易感性降低相关。D1116 G/N/Y突变与SJ 733敏感性降低相关，密码子223和1116突变与PA 92和SJ 733敏感性降低相关。在所有这些情况下，野生型（WT）和突变型寄生虫的亲和性的绝对差异是适度的。从混合田间分离株中分离的克隆分析一致地鉴定突变体克隆比WT更不敏感。对来自其他地点的分离株的分析表明，乌干达各地存在G223 S和D1116 G/N/Y突变。我们的研究结果表明，在乌干达流行的疟疾寄生虫在PfATP 4中有许多多态性，并且适度降低对PfATP 4抑制剂的敏感性与乌干达寄生虫中存在的一些突变有关。
Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessedex vivosusceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda, from 2016 to 2019. Median IC50s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing ofpfatp4for 218 of these isolates demonstrated many nonsynonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K (16%), and D1116G/N/Y (16%). The G223S mutation was associated with decreased susceptibility to SJ733, PA92, and KAE609. The D1116G/N/Y mutations were associated with decreased susceptibility to SJ733, and the presence of mutations at both codons 223 and 1116 was associated with decreased susceptibility to PA92 and SJ733. In all of these cases, absolute differences in susceptibilities of wild-type (WT) and mutant parasites were modest. Analysis of clones separated from mixed field isolates consistently identified mutant clones as less susceptible than WT. Analysis of isolates from other sites demonstrated the presence of the G223S and D1116G/N/Y mutations across Uganda. Our results indicate that malaria parasites circulating in Uganda have a number of polymorphisms in PfATP4 and that modestly decreased susceptibility to PfATP4 inhibitors is associated with some mutations now present in Ugandan parasites.