Discussion

Many drugs exert their activity by interfering with cellular metabolism. Moreover, alterations to metabolism can underpin drug resistance. Untargeted metabolomics enables analysis of metabolism in any biological system and is capable of identifying areas of metabolism which are perturbed in an unbiased manner. We have applied metabolomics to understand more about the modes of action of numerous antimicrobial agents. In trypanosomes, for example, the inhibition of ornithine decarboxylase by eflornithine was readily visible and resistance to this drug was shown to relate to loss of drug uptake due to deletion of the gene encoding a transporter responsible for uptake. In Leishmania, combining metabolomics analysis with genome sequencing has identified a gene responsible for resistance to amphotericin B. We have also shown how a number of other drugs exert their activity against protozoa and bacteria. The untargeted metabolomics platform has also been shown to be capable of identifying biomarkers of infection and the stage of disease in African trypanosomiasis.