Using Metabolomics for Elucidating the Mechanisms Related to Tuberculosis Treatment Failure
Laneke de Villiers and Du Toit Loots
Affiliation: School for Physical and Chemical Sciences, Centre for Human Metabonomics, North-West University (Potchefstroom Campus), Private Bag x6001, Box 269, Potchefstroom, South Africa, 2531.
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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