The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations.
The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations.
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DOI：
10.1111/nyas.12662
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发表时间：
2015-04
影响因子：
5.2
通讯作者：
Kirkman L
中科院分区：
文献类型：
--
作者：
Heinberg A;Kirkman L
针对叶酸合成途径的药物对多种病原体具有悠久的有效性。作为抗疟药，抗叶酸药物安全且耐受性良好，但耐药性很快出现，并且即使药物压力降低，耐药性仍然持续存在。恶性疟原虫耐药性的主要决定因素是磺胺多辛-乙胺嘧啶 (SP) 组合所针对的二氢叶酸合成酶 (DHPS) 和二氢叶酸还原酶 (DHFR) 中已被充分描述的点突变。最近的工作强调了额外的寄生虫适应对抗叶酸剂耐药性的贡献。事实上，抗叶酸寄生虫的进化是多方面且复杂的。寄生虫叶酸合成途径中第一种酶 GTP-环水解酶 (GCH1) 的基因扩增与抗性寄生虫密切相关，并可能有助于抗性寄生虫的持续存在。进一步了解寄生虫如何调节叶酸途径的通量对于进一步开发针对这一关键合成途径的替代药物非常重要。
Drugs that target the folate synthesis pathway have a long history of effectiveness against a variety of pathogens. As antimalarials, the antifolates were safe and well tolerated, but resistance emerged quickly and has persisted even with decreased drug pressure. The primary determinants of resistance in Plasmodium falciparum are well-described point mutations in the enzymes dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) targeted by the combination sulfadoxine–pyrimethamine (SP). Recent work has highlighted the contributions of additional parasite adaptation to antifolate resistance. In fact, the evolution of antifolate-resistant parasites is multifaceted and complex. Gene amplification of the first enzyme in the parasite folate synthesis pathway, GTP-cyclohydrolase (GCH1) is strongly associated with resistant parasites and potentially contributes to persistence of resistant parasites. Further understanding of how parasites adjust flux through the folate pathway is important to the further development of alternative agents targeting this crucial synthesis pathway.
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影响因子：
4.4
作者：
Jiang H;Yi M;Mu J;Zhang L;Ivens A;Klimczak LJ;Huyen Y;Stephens RM;Su XZ
通讯作者：
Su XZ
影响因子：
12.3
作者：
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通讯作者：
Wirth, Dyann F.
影响因子：
2.7
作者：
Hyde, JE
通讯作者：
Hyde, JE
影响因子：
10.7
作者：
Brown, Kyle M.;Costanzo, Marna S.;Hartl, Daniel L.
通讯作者：
Hartl, Daniel L.
DOI：
10.1073/pnas.0905922106
发表时间：
2009-07-21
影响因子：
11.1
作者：
Lozovsky, Elena R.;Chookajorn, Thanat;Hartl, Daniel L.
通讯作者：
Hartl, Daniel L.