Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin
Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin
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DOI：
10.1093/infdis/jiw304
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发表时间：
2016-10-01
影响因子：
6.4
通讯作者：
Odom, Audrey R.
中科院分区：
文献类型：
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作者：
Guggisberg, Ann M.;Sundararaman, Sesh A.;Odom, Audrey R.
面对新出现的对青蒿素联合疗法的耐药性，需要新的抗疟疾疗法。先前的一项研究发现，莫桑比克患有无并发症恶性疟原虫疟疾的儿童在与氟米多霉素-克林霉素联合治疗后7天的治愈率很高。然而，由于寄生虫复发，28天治愈率很低（45.9%）。我们试图确定寄生虫复发的任何遗传变化。为此，我们采用选择性全基因组扩增方法从血斑DNA样本中扩增寄生虫基因组。对来自预处理和复发后样本的寄生虫基因组进行全基因组测序以鉴定核苷酸变异。我们的数据不支持在氟米霉素-克林霉素治疗后导致复发的基因改变的存在。此外，我们发现先前描述的这些药物的耐药等位基因并不代表复发的生物标志物。未来的研究应继续优化fosmidomycin组合作为抗疟疾疗法的使用。
Novel antimalarial therapies are needed in the face of emerging resistance to artemisinin combination therapies. A previous study found a high cure rate in Mozambican children with uncomplicated Plasmodium falciparum malaria 7 days after combination treatment with fosmidomycin-clindamycin. However, 28-day cure rates were low (45.9%), owing to parasite recrudescence. We sought to identify any genetic changes underlying parasite recrudescence. To this end, we used a selective whole-genome amplification method to amplify parasite genomes from blood spot DNA samples. Parasite genomes from pretreatment and postrecrudescence samples were subjected to whole-genome sequencing to identify nucleotide variants. Our data did not support the existence of a genetic change responsible for recrudescence following fosmidomycin-clindamycin treatment. Additionally, we found that previously described resistance alleles for these drugs do not represent biomarkers of recrudescence. Future studies should continue to optimize fosmidomycin combinations for use as antimalarial therapies.