Antimicrobial agents and chemotherapy, 2016-04, Vol.60 (4), p.2281-2291
2016
Details
- Autor(en) / Beteiligte
- Titel
- Untargeted Metabolomics To Ascertain Antibiotic Modes of Action
- Ist Teil von
- Antimicrobial agents and chemotherapy, 2016-04, Vol.60 (4), p.2281-2291
- Ort / Verlag
- United States: American Society for Microbiology
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0066-4804eISSN: 1098-6596DOI: 10.1128/AAC.02109-15Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4808186
- Format
- –
- Schlagworte
- Acyltransferases - antagonists & inhibitors, Acyltransferases - genetics, Acyltransferases - metabolism, Adenosine - metabolism, Adenosine - pharmacology, Anti-Bacterial Agents, Anti-Bacterial Agents - metabolism, Anti-Bacterial Agents - pharmacology, Carbonyl Cyanide m-Chlorophenyl Hydrazone - metabolism, Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology, Ceftazidime - metabolism, Ceftazidime - pharmacology, Cell Wall - chemistry, Cell Wall - drug effects, Cell Wall - metabolism, Chromatography, Liquid, DNA, Bacterial - antagonists & inhibitors, DNA, Bacterial - biosynthesis, Escherichia coli, Escherichia coli - drug effects, Escherichia coli - genetics, Escherichia coli - metabolism, Fosfomycin - analogs & derivatives, Fosfomycin - metabolism, Fosfomycin - pharmacology, Gene Expression, HEK293 Cells, Humans, Hydroxamic Acids - metabolism, Hydroxamic Acids - pharmacology, Mass Spectrometry, Mechanisms of Action: Physiological Effects, Metabolome, Metabolome - drug effects, Metabolomics, Nucleoside-Phosphate Kinase - antagonists & inhibitors, Nucleoside-Phosphate Kinase - genetics, Nucleoside-Phosphate Kinase - metabolism, Pyrimidines - metabolism, Pyrimidines - pharmacology, Terpenes - antagonists & inhibitors, Terpenes - metabolism, Threonine - analogs & derivatives, Threonine - metabolism, Threonine - pharmacology, Triclosan - metabolism, Triclosan - pharmacology