Mycobacterium tuberculosis (Mtb) is considered to be a devastating pathogen worldwide, affecting millions of people globally. Several drugs targeting distinct pathways are utilized for the treatment of tuberculosis. Despite the monumental efforts being directed at the discovery of drugs for Mtb, the pathogen has also developed mechanisms to evade the drug action and host processes. Rifampicin was an early anti-tuberculosis drug, and is still being used as the first line of treatment. This study was carried out in order to characterize the in-depth rifampicin-mediated metabolic changes in Mtb, facilitating a better understanding of the physiological processes based on the metabolic pathways and predicted protein interactors associated with the dysregulated metabolome. Although there are various metabolomic studies that have been carried out on rifampicin mutants, this is the first study that reports a large number of significantly altered metabolites in wild type Mtb upon rifampicin treatment. In this study, a total of 173 metabolites, associated with pyrimidine, purine, arginine, phenylalanine, tyrosine, and tryptophan metabolic pathways, were significantly altered by rifampicin. The predicted host protein interactors of the rifampicin-dysregulated Mtb metabolome were implicated in transcription, inflammation, apoptosis, proteolysis, and DNA replication. Further, tricarboxylic acidcycle metabolites, arginine, and phosphoenolpyruvate were validated by multiple-reaction monitoring. This study provides a comprehensive list of altered metabolites that serves as a basis for understanding the rifampicin-mediated metabolic changes, and associated functional processes, in Mtb, which holds therapeutic potential for the treatment of Mtb.

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