Characterization and prediction of the mechanism of action of antibiotics through NMR metabolomics

BMC Microbiology

Research Article

Hans J. Vogel¹  Gavin E. Duggan¹  Christina Große²  Ute Neugebauer²  Karen K. H. Poon³  Lori Zbytnuik³  Karen Methling⁴  Verena Hoerr⁵  Bettina Löffler⁶ 

[1] Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, Canada;Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany;Leibniz Institute of Photonic Technology, Jena, Germany;Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada;Institute of Biochemistry, University of Greifswald, Greifswald, Germany;Institute of Medical Microbiology, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany;Institute of Medical Microbiology, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany;Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany;

关键词: Metabolomics;    H NMR spectroscopy;    Intracellular fingerprinting;    Extracellular footprinting;    Mode of action of antibiotics;    Multivariate data analysis;    Prediction of antibiotic classes;   

DOI  :  10.1186/s12866-016-0696-5

 received in 2015-07-07, accepted in 2016-04-27,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe emergence of antibiotic resistant pathogenic bacteria has reduced our ability to combat infectious diseases. At the same time the numbers of new antibiotics reaching the market have decreased. This situation has created an urgent need to discover novel antibiotic scaffolds. Recently, the application of pattern recognition techniques to identify molecular fingerprints in ‘omics’ studies, has emerged as an important tool in biomedical research and laboratory medicine to identify pathogens, to monitor therapeutic treatments or to develop drugs with improved metabolic stability, toxicological profile and efficacy. Here, we hypothesize that a combination of metabolic intracellular fingerprints and extracellular footprints would provide a more comprehensive picture about the mechanism of action of novel antibiotics in drug discovery programs.ResultsIn an attempt to integrate the metabolomics approach as a classification tool in the drug discovery processes, we have used quantitative 1H NMR spectroscopy to study the metabolic response of Escherichia coli cultures to different antibiotics. Within the frame of our study the effects of five different and well-known antibiotic classes on the bacterial metabolome were investigated both by intracellular fingerprint and extracellular footprint analysis. The metabolic fingerprints and footprints of bacterial cultures were affected in a distinct manner and provided complementary information regarding intracellular and extracellular targets such as protein synthesis, DNA and cell wall. While cell cultures affected by antibiotics that act on intracellular targets showed class-specific fingerprints, the metabolic footprints differed significantly only when antibiotics that target the cell wall were applied. In addition, using a training set of E. coli fingerprints extracted after treatment with different antibiotic classes, the mode of action of streptomycin, tetracycline and carbenicillin could be correctly predicted.ConclusionThe metabolic profiles of E. coli treated with antibiotics with intracellular and extracellular targets could be separated in fingerprint and footprint analysis, respectively and provided complementary information. Based on the specific fingerprints obtained for different classes of antibiotics, the mode of action of several antibiotics could be predicted. The same classification approach should be applicable to studies of other pathogenic bacteria.

【 授权许可】

CC BY   
© Hoerr et al. 2016