A conserved metabolic signature associated with response to fast-acting anti-malarial agents.
A conserved metabolic signature associated with response to fast-acting anti-malarial agents.
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DOI：
10.1128/spectrum.03976-22
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发表时间：
2023-12-12
影响因子：
3.7
通讯作者：
Waters, Andrew P.
中科院分区：
文献类型：
--
作者：
Simwela, Nelson V.;Guiguemde, W. Armand;Straimer, Judith;Regnault, Clement;Stokes, Barbara H.;Tavernelli, Luis E.;Yokokawa, Fumiaki;Taft, Benjamin;Diagana, Thierry T.;Barrett, Michael P.;Waters, Andrew P.
表征从高通量表型筛选中产生的抗疟疾化合物的作用模式，是理解寄生虫如何对这些药物产生抗药性的核心。在这里，我们使用非靶向代谢组学来告知诺华热带病研究所(NITD)正在开发的具有不同杀灭速度的抗疟疾先导的作用机制。药物治疗时疟疾寄生虫代谢物的时间分辨的全球变化用基于液相色谱的质谱仪进行了量化，并与未经治疗的对照组进行了比较。使用这种方法，我们证实了先前报道的快杀(2.5小时)药物双氢青蒿素(DHA)和慢杀阿托瓦酮的代谢组学特征。来自咪唑并哌嗪类(IZP)类NITD的慢效抗疟疾先导GNF179在相同的2.5h药物暴露时间窗口内，几乎没有或几乎没有引起疟疾寄生虫的代谢变化。相比之下，速杀药物DHA和螺吲哚酮(NITD246)在动力学和含量方面都产生了相似的代谢谱。DHA和NITD246引起的多肽丢失与血红蛋白分解代谢的中断一致，也干扰了嘧啶的生物合成途径。最近描述的5-芳基-2-氨基-咪唑类抗疟疾药物中的两个成员也表现出快速作用的特征，其特征是多肽丢失表明血红蛋白分解代谢受阻。我们的筛查显示，结构无关的快速作用抗疟疾化合物在疟原虫中产生类似的生化特征，指向与寄生虫快速死亡相关的常见机制。这些特征可以用来识别和可能预测其他快速作用的候选药物的作用模式。在疟疾药物发现中，了解先导化合物的作用模式很重要，因为它有助于预测当这些药物最终部署时，现场可能出现抗药性。在这项研究中，我们使用代谢组学技术来表征NITD开发流水线中抗疟疾药物候选的潜在靶点。我们发现，属于螺吲哚和咪唑噻二唑类的NITD快效先导在药物暴露的疟疾寄生虫中诱导了一个共同的生化主题，这类似于另一种快速作用的临床可用药物DHA。这些生化特征在作用较慢的NITD导联(GNF17)中缺失，表明血红蛋白消化和抑制嘧啶途径是这些药物的潜在作用点。这些生化主题可用于在未来的药物发现计划中识别和告知具有相似特征的快速候选药物的作用模式。
Characterizing the mode of action of anti-malarial compounds that emerge from high-throughput phenotypic screens is central to understanding how parasite resistance to these drugs can emerge. Here, we have employed untargeted metabolomics to inform on the mechanism of action of anti-malarial leads with different speed of kill profiles being developed by the Novartis Institute of Tropical Diseases (NITD). Time-resolved global changes in malaria parasite metabolite profiles upon drug treatment were quantified using liquid chromatography-based mass spectrometry and compared to untreated controls. Using this approach, we confirmed previously reported metabolomics profiles of the fast-killing (2.5 h) drug dihydroartemisinin (DHA) and the slower killing atovaquone. A slow-acting anti-malarial lead from NITD of imidazolopiperazine (IZP) class, GNF179, elicited little or no discernable metabolic change in malaria parasites in the same 2.5-h window of drug exposure. In contrast, fast-killing drugs, DHA and the spiroindolone (NITD246), elicited similar metabolomic profiles both in terms of kinetics and content. DHA and NITD246 induced peptide losses consistent with disruption of hemoglobin catabolism and also interfered with the pyrimidine biosynthesis pathway. Two members of the recently described class of anti-malarial agents of the 5-aryl-2-amino-imidazothiadiazole class also exhibited a fast-acting profile that featured peptide losses indicative of disrupted hemoglobin catabolism. Our screen demonstrates that structurally unrelated, fast-acting anti-malarial compounds generate similar biochemical signatures in Plasmodium pointing to a common mechanism associated with rapid parasite death. These profiles may be used to identify and possibly predict the mode of action of other fast-acting drug candidates. In malaria drug discovery, understanding the mode of action of lead compounds is important as it helps in predicting the potential emergence of drug resistance in the field when these drugs are eventually deployed. In this study, we have employed metabolomics technologies to characterize the potential targets of anti-malarial drug candidates in the developmental pipeline at NITD. We show that NITD fast-acting leads belonging to spiroindolone and imidazothiadiazole class induce a common biochemical theme in drug-exposed malaria parasites which is similar to another fast-acting, clinically available drug, DHA. These biochemical features which are absent in a slower acting NITD lead (GNF17) point to hemoglobin digestion and inhibition of the pyrimidine pathway as potential action points for these drugs. These biochemical themes can be used to identify and inform on the mode of action of fast drug candidates of similar profiles in future drug discovery programs.
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影响因子：
4.8
作者：
Cobbold, Simon A.;Vaughan, Ashley M.;Llinas, Manuel
通讯作者：
Llinas, Manuel
DOI：
10.1073/pnas.1414221111
发表时间：
2014-12-16
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
12.3
作者：
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通讯作者：
Wirth, Dyann F.
影响因子：
3
作者：
Kim, Charles C.;Wilson, Emily B.;DeRisi, Joseph L.
通讯作者：
DeRisi, Joseph L.
DOI：
10.1073/pnas.1600459113
发表时间：
2016-02-23
影响因子：
11.1
作者：
Ismail, Hanafy M.;Barton, Victoria;Ward, Stephen A.
通讯作者：
Ward, Stephen A.