Pathogen-specific drug metabolism in tuberculosis: Enzymes, metabolic pathways, and new horizons in therapeutic development

Tuberculosis (TB) remains a major public health problem with increased incidence of drug-resistant TB due to failure of existing treatments. Current anti-TB drugs are mainly directed at targeting important biochemical pathways in the Mtb with the biotransformation of drugs through hepatic metabolism. However, new proof indicates that Mtb can directly contribute to drug metabolism, therefore determining both the effectiveness and the resistance of a therapeutic agent. This review aims to explore the mechanism of action of Mtb mediated drug biotransformation, the several enzymes it contains and new metabolic pathway by which the pathogen could alter, neutralize or even stimulate antitubercular agents. Static liver-based models of metabolism are then compared to pathogen-based models to give a deeper understanding of how the host and pathogen jointly determine the final outcome and efficacy of the drug. In addition, the Mtb driven biotransformation, causes impact Mtb metabolism on pharmacokinetics, drug half-life, and bioavailability, and the potential to develop new therapeutic approaches are also elaborated. This review also discusses possible directions in drug discovery by identifying Mtb-specific enzymes, using combination therapy, which affects the host and pathogen's metabolism, and using metabolomic and computational analysis for pathway identification. The potential lies in applying pathogen-specific knowledge to TB drug development to address adaptive resistance, improve on drug dosing regimens, and improve treatment outcomes. Additionally, host-directed therapies (HDTs) and the concept of developing drugs with dual activity are suggested as possible new strategies in TB control. Holders of co-culture systems, organoids, and machine learning-driven metabolomics are considered as advanced models for demystifying Mtb drug metabolism. These findings emphasize the need for a shift towards precision medicine approach to TB therapy to consider the kinetic nature and Mtb metabolism patterns in relation to human health.