Novel insights into the pharmacometabonomics of first-line tuberculosis drugs relating to metabolism, mechanism of action and drug-resistance

The World Health Organization recommends the directly observed therapy short-course (DOTS) regimen, a combination of four first-line antibiotics (isoniazid, rifampicin, pyrazinamide and ethambutol), for the treatment of active pulmonary tuberculosis (TB). However, despite the fact that this treatment regimen is commonly used worldwide, the metabolism and anti-bacterial mechanisms of these drugs are not yet fully understood. This lack of information ultimately contributes to the poor patient compliance and the subsequent treatment failure and post treatment relapse seen in some TB patients. Pharmacometabonomics, the latest addition to the omics research domain, focuses on the identification of drug-induced metabolome variations. The observed metabolite changes can be used to better understand drug metabolism, drug action and drug-resistance mechanisms. In this review, we summarize the generally known biological mechanisms of the first-line TB drugs included in the DOTS program, and we additionally elaborate on the contribution that pharmacometabonomics has made to the expansion of this knowledge.