Deciphering the mode of action (MOA) of new antibiotics discovered through phenotypic screening is of increasing importance. Metabolomics offers a potentially rapid and cost-effective means of identifying modes of action of drugs whose effects are mediated through changes in metabolism. Metabolomics techniques also collect data on off-target effects and drug modifications. Here, we present data from an untargeted liquid chromatography-mass spectrometry approach to identify the modes of action of eight compounds: 1-[3-fluoro-4-(5-methyl-2,4-dioxo-pyrimidin-1-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea (AZ1), 2-(cyclobutylmethoxy)-5'-deoxyadenosine, triclosan, fosmidomycin, CHIR-090, carbonyl cyanidem-chlorophenylhydrazone (CCCP), 5-chloro-2-(methylsulfonyl)-N-(1,3-thiazol-2-yl)-4-pyrimidinecarboxamide (AZ7), and ceftazidime. Data analysts were blind to the compound identities but managed to identify the target as thymidylate kinase for AZ1, isoprenoid biosynthesis for fosmidomycin, acyl-transferase for CHIR-090, and DNA metabolism for 2-(cyclobutylmethoxy)-5'-deoxyadenosine. Changes to cell wall metabolites were seen in ceftazidime treatments, although other changes, presumably relating to off-target effects, dominated spectral outputs in the untargeted approach. Drugs which do not work through metabolic pathways, such as the proton carrier CCCP, have no discernible impact on the metabolome. The untargeted metabolomics approach also revealed modifications to two compounds, namely, fosmidomycin and AZ7. An untreated control was also analyzed, and changes to the metabolome were seen over 4 h, highlighting the necessity for careful controls in these types of studies. Metabolomics is a useful tool in the analysis of drug modes of action and can complement other technologies already in use.

中文翻译：

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用于确定抗生素作用方式的非靶向代谢组学。

解释通过表型筛选发现的新抗生素的作用方式（MOA）越来越重要。代谢组学提供了一种潜在的快速且经济高效的方法，可确定通过代谢变化介导其作用的药物的作用方式。代谢组学技术还收集脱靶效应和药物修饰方面的数据。在这里，我们提供了来自非目标液相色谱-质谱法的数据，以鉴定八种化合物的作用模式：1- [3-氟-4-（5-甲基-2,4-二氧代嘧啶-1-基）苯基] -3- [2-（三氟甲基）苯基]脲（AZ1），2-（环丁基甲氧基）-5'-脱氧腺苷，三氯生，膦霉素，CHIR-090，羰基氰化物-氯苯基hydr（CCCP），5-氯-2 -（甲基磺酰基）-N-（1,3-噻唑-2-基）-4-嘧啶羧酰胺（AZ7）和头孢他啶。数据分析人员对化合物的身份视而不见，但设法将目标物识别为AZ1的胸苷酸激酶，fosmidomycin的类异戊二烯生物合成，CHIR-090的酰基转移酶以及2-（环丁基甲氧基）-5'-脱氧腺苷的DNA代谢。在头孢他啶治疗中观察到细胞壁代谢物的变化，尽管其他变化可能与脱靶作用有关，但在非靶向方法中占主导地位。不能通过代谢途径起作用的药物，例如质子载体CCCP，对代谢组没有明显的影响。非靶向代谢组学方法还揭示了对两种化合物的修饰，即磷霉素和AZ7。还对未经处理的对照进行了分析，并在4小时内观察到了代谢组的变化，这突出表明在这些类型的研究中必须进行仔细对照的必要性。