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Abstract：
Sulfadoxine-pyrimethamine (SP) resistance impairs the efficacy of antimalarial drugs. Monitoring molecular markers in exported malaria infections provides an efficient way to trace the emergence of drug resistance in countries where malaria is endemic. Molecular markers in Pfdhfr and Pfdhps of 237 Plasmodium falciparum infections imported from central Africa between 2016 and 2021 were detected. The spatial and temporal distributions of Pfdhfr and Pfdhps mutations were analyzed. A high prevalence of Pfdhfr single-nucleotide polymorphisms (SNPs) (~92.34% to 99.10%) and a high frequency of the triple mutation haplotype I51R59N108 were observed. Cameroon, Equatorial Guinea, and Gabon showed a higher frequency (~96.61% to 100.00%) of I51R59N108 than other countries (~71.11% to 88.10%). The prevalence of C59R and I51R59N108 increased while that of other SNPs or haplotypes did not fluctuate greatly from 2016 to 2021. Large proportions of Pfdhps SNPs (A437G and K540E) were demonstrated. The SNP distribution of Pfdhps differed between countries, with S436A dominating in northern countries and A437G dominating in others. The proportions of I431V, A437G, and the triple mutant haplotype declined between 2016 and 2021, whereas the prevalence of the single mutant haplotype rose from 61.60% to 73.68%. Combinations of Pfdhfr-Pfdhps alleles conferring partial resistance, full resistance, and superresistance to SP, as defined in the text, were detected in 63.64%, 8.64%, and 0.91% of the samples, respectively. The octuple Pfdhfr-Pfdhps allele (I51R59N108-V431A436G437K540G581S613) was seen in 5.00% of the samples. We demonstrated the wide geographic spread and increasing trends in highly SP-resistant Pfdhfr genes and varying spatial patterns of Pfdhps mutants across countries in central Africa. The high prevalences of partially resistant, fully resistant, and superresistant Pfdhfr-Pfdhps combinations observed here indicated impaired SP efficacy. Increased molecular surveillance is required to monitor the changing status of the Pfdhfr and Pfdhps genes. IMPORTANCE Monitoring drug resistance is important for malaria control because its early detection enables timely action to prevent its spread and mitigate its impact. The wide geographic spread and the increasing trend of highly resistant Pfdhfr genes between 2016 and 2021 found in our study are worrisome and emphasize the urgency to monitor their updated status in central Africa. This study also illustrated the wide spread of the novel mutant Pfdhps I431V as well as the high prevalence of \"partially resistant,\" \"fully resistant,\" and \"superresistant\" Pfdhfr-Pfdhps combinations, indicating the urgent concern for SP efficacy in central Africa. These findings are alarming in central African countries where malaria is endemic, where SP was is widely used for the intermittent preventive treatment of malaria in pregnancy (IPTp) and the intermittent preventive treatment of malaria in infants below 5 years of age (IPTi), and urge enhanced molecular surveillance and responses to the threat of drug resistance.
摘要：
磺胺多辛-乙胺嘧啶（SP）耐药性会损害抗疟药的疗效。监测出口疟疾感染中的分子标志物提供了一种有效的方法来追踪疟疾流行国家耐药性的出现。检测到了2016年至2021年间从中部非洲进口的237例恶性疟原虫感染的Pfdhfr和Pfdhps的分子标记。分析了Pfdhfr和Pfdhps突变的时空分布。观察到Pfdhfr单核苷酸多态性（SNP）的高患病率（〜92.34％至99.10％）和三重突变单倍型I51R59N108的高频率。喀麦隆,赤道几内亚,加蓬显示I51R59N108的频率（〜96.61％至100.00％）高于其他国家（〜71.11％至88.10％）。从2016年到2021年，C59R和I51R59N108的患病率增加，而其他SNP或单倍型的患病率没有很大的波动。证明了大比例的PfdhpsSNP(A437G和K540E)。Pfdhps的SNP分布在国家之间有所不同，S436A在北方国家占主导地位，A437G在其他国家占主导地位。I431V的比例，A437G,三突变单倍型在2016年至2021年期间下降，而单突变单倍型的患病率从61.60%上升到73.68%。赋予部分抗性的Pfdhfr-Pfdhps等位基因的组合，全阻力,和对SP的超强抗性，如文中所定义，在63.64%中检测到，8.64%，和0.91%的样品，分别。在5.00%的样品中观察到八位Pfdhfr-Pfdhps等位基因(I51R59N108-V431A436G437K540G581S613)。我们证明了中部非洲各国高度抗SP的Pfdhfr基因的广泛地理分布和增加趋势以及Pfdhps突变体的不同空间模式。部分抗性的高流行率，完全抵抗,此处观察到的超抗性Pfdhfr-Pfdhps组合表明SP功效受损。需要增加分子监测来监测Pfdhfr和Pfdhps基因的变化状态。重要性监测耐药性对疟疾控制很重要，因为它的早期发现能够及时采取行动防止其传播并减轻其影响。在我们的研究中发现，2016年至2021年间，高抗性Pfdhfr基因的广泛地理分布和增加趋势令人担忧，并强调了监测其在中非最新状态的紧迫性。这项研究还说明了新突变体PfdhpsI431V的广泛传播以及部分抗性的高患病率，“\”完全抵抗，\"和\"超抗\"Pfdhfr-Pfdhps组合，表明中部非洲对SP疗效的迫切关注。这些发现在疟疾流行的中非国家令人震惊，其中SP被广泛用于妊娠期疟疾的间歇性预防性治疗（IPTp）和5岁以下婴儿疟疾的间歇性预防性治疗（IPTi），并敦促加强分子监测和应对耐药性威胁。
