Metabolic adjustments of blood-stage Plasmodium falciparum in response to sublethal pyrazoleamide exposure.
Metabolic adjustments of blood-stage Plasmodium falciparum in response to sublethal pyrazoleamide exposure.
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DOI：
10.1038/s41598-022-04985-7
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发表时间：
2022-01-21
影响因子：
4.6
通讯作者：
Wallqvist A
中科院分区：
文献类型：
--
作者：
Tewari SG;Kwan B;Elahi R;Rajaram K;Reifman J;Prigge ST;Vaidya AB;Wallqvist A
由于抗疟药物经常丧失耐药性，因此需要新的靶点、药物和联合疗法，以确保当前和未来对策的可用性。吡唑酰胺类药物属于一类新型抗疟药物，可破坏钠离子稳态，尽管这种破坏在恶性疟原虫中的确切后果仍在调查中。体外实验表明，携带代谢酶PfATP 4突变的寄生虫对吡唑酰胺化合物产生耐药性。然而，允许突变寄生虫逃避吡唑胺治疗的潜在机制尚不清楚。在这里，我们首先进行了实验，以确定亚致死剂量的吡唑酰胺化合物（PA 21 A092），导致一个红细胞内发育周期（IDC）的生长显着减少。在此药物浓度下，我们在IDC期间的多个时间点收集转录组学和代谢组学数据，以量化经处理寄生虫中的基因和代谢物水平变化。为了探索吡唑酰胺治疗对寄生虫代谢的影响，我们将时间分辨组学数据与恶性疟原虫的代谢网络模型相结合。我们发现，药物处理的寄生虫调整碳水化合物代谢，以提高肌醇的合成-磷脂酰肌醇生物合成的前体。这种代谢适应导致通过磷酸戊糖途径的代谢物通量减少，导致RNA合成速率降低和氧化应激增加。我们的模型分析表明，增强肌醇合成的下游后果可能是调整的基础，可能导致恶性疟原虫暴露于亚致死剂量的吡唑酰胺药物的耐药性出现。
Due to the recurring loss of antimalarial drugs to resistance, there is a need for novel targets, drugs, and combination therapies to ensure the availability of current and future countermeasures. Pyrazoleamides belong to a novel class of antimalarial drugs that disrupt sodium ion homeostasis, although the exact consequences of this disruption in Plasmodium falciparum remain under investigation. In vitro experiments demonstrated that parasites carrying mutations in the metabolic enzyme PfATP4 develop resistance to pyrazoleamide compounds. However, the underlying mechanisms that allow mutant parasites to evade pyrazoleamide treatment are unclear. Here, we first performed experiments to identify the sublethal dose of a pyrazoleamide compound (PA21A092) that caused a significant reduction in growth over one intraerythrocytic developmental cycle (IDC). At this drug concentration, we collected transcriptomic and metabolomic data at multiple time points during the IDC to quantify gene- and metabolite-level alterations in the treated parasites. To probe the effects of pyrazoleamide treatment on parasite metabolism, we coupled the time-resolved omics data with a metabolic network model of P. falciparum. We found that the drug-treated parasites adjusted carbohydrate metabolism to enhance synthesis of myoinositol—a precursor for phosphatidylinositol biosynthesis. This metabolic adaptation caused a decrease in metabolite flux through the pentose phosphate pathway, causing a decreased rate of RNA synthesis and an increase in oxidative stress. Our model analyses suggest that downstream consequences of enhanced myoinositol synthesis may underlie adjustments that could lead to resistance emergence in P. falciparum exposed to a sublethal dose of a pyrazoleamide drug.
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DOI：
10.1126/science.1193225
发表时间：
2010-09-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Rottmann M;McNamara C;Yeung BK;Lee MC;Zou B;Russell B;Seitz P;Plouffe DM;Dharia NV;Tan J;Cohen SB;Spencer KR;González-Páez GE;Lakshminarayana SB;Goh A;Suwanarusk R;Jegla T;Schmitt EK;Beck HP;Brun R;Nosten F;Renia L;Dartois V;Keller TH;Fidock DA;Winzeler EA;Diagana TT
通讯作者：
Diagana TT
影响因子：
4
作者：
Flannery, Erika L.;McNamara, Case W.;Kim, Sang Wan;Kato, Tomoyo Sakata;Li, Fengwu;Teng, Christine H.;Gagaring, Kerstin;Manary, Micah J.;Barboa, Rachel;Meister, Stephan;Kuhen, Kelli;Vinetz, Joseph M.;Chatterjee, Arnab K.;Winzeler, Elizabeth A.
通讯作者：
Winzeler, Elizabeth A.
DOI：
10.1073/pnas.1414221111
发表时间：
2014-12-16
影响因子：
11.1
作者：
Belen Jimenez-Diaz, Maria;Ebert, Daniel;Guy, R. Kiplin
通讯作者：
Guy, R. Kiplin
DOI：
10.1002/bms.1200131004
发表时间：
1986-10-01
期刊：
BIOMEDICAL AND ENVIRONMENTAL MASS SPECTROMETRY
影响因子：
--
作者：
KASSEL, DB;MARTIN, M;SWEELEY, CC
通讯作者：
SWEELEY, CC
DOI：
10.1016/s2221-1691(11)60034-8
发表时间：
2011-06-01
影响因子：
1.7
作者：
Krungkrai, Sudaratana R.;Krungkrai, Jerapan
通讯作者：
Krungkrai, Jerapan