Using Metabolomics for Elucidating the Mechanisms Related to Tuberculosis Treatment Failure

Laneke   de   Villiers; Du   Toit   Loots

doi:10.2174/2213235X113016660006

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis is a highly infectious disease, responsible for 1.4 million deaths annually. Unfortunately, the latest reports of treatment outcomes for patients using the current anti-TB drugs are disappointing, considering the high treatment failure rates. This has been ascribed to a number of factors, including, amongst others: (1) variable individual metabolism (including xenobiotic metabolism, drug malabsorption and drugdrug interactions), (2) drug resistance by the infectious organism and (3) non-adherence to the treatment program, especially due to the associated drug side-effects. Despite this however, only two new drugs have been approved by the FDA since 1962. Thus, it is clear that new strategies are needed for the better elucidation of in vivo anti-TB drug mechanisms and their associated side-effects, and the mechanisms by which the infectious organism develops drug resistance. To this end, the relatively new research approach termed ‘metabolomics’, shows promising results through its capacity for identifying new drug markers, or metabolic pathways related to these contributing factors. Metabolomics refers to the unbiased identification and quantification of all metabolites (products of bio-molecular processes) present in a biological system, using highly selective and sensitive analytical methods. The application of metabolomics, for biomarker discovery, is based on the principle that an external stimulus, such as TB disease or infection, an anti-TB drug, or a mutation resulting in drug resistance, may disrupt normal metabolism, altering the overall physiological status of an organism or host, and these metabolic changes are specific to the perturbation investigated and not due to overall inflammation or disease process. Analyses of these altered metabolic pathways, may subsequently shed new light on the mechanisms associated with the causes of treatment failure, and ultimately lead to new treatment strategies which may most likely be aimed at targeting specific metabolic pathways in M. tuberculosis, and/or the genes/proteins associated with these.

Keywords: Drug-drug interactions, drug mechanisms, metabolomics, treatment failure, tuberculosis, xenobiotic metabolism.

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