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Intrabacterial drug metabolism in Mycobacterium tuberculosis

V Maes(1,2,3) C A Pérez(1) J Masschelein(2,3) A Van Vlaslaer(1)

1:Johnson & Johnson Innovative Medicine; 2:Vlaams instituut voor Biotechnologie (VIB); 3:KU Leuven

There is an urgent need for new and smarter drugs to shorten TB treatment and end TB. To design these drugs, a key factor is the interaction between the compound and target bacteria, with one aspect being the metabolism of compounds within Mycobacterium tuberculosis (Mtb). That is why this project aims to study intrabacterial drug metabolism (IBDM) in Mtb from two perspectives: first the main chemical changes and second, the involved pathways or genes responsible for this metabolism. Altogether, this knowledge will open up new avenues for developing smarter anti-TB drugs that circumvent intrabacterial drug metabolism or use it to their advantage.

Currently, we are screening known anti-TB compounds to evaluate drug metabolism in Mtb by UHPLC-MS. The first step is to evaluate depletion of the intact drug molecule. Next, for the compounds showing potential metabolism, we perform MS/MS and analyze the data with molecular networking to visualize the biotransformations and elucidate the structures of the metabolic products. With this project we aim to fill the gap in metabolism studies for the ADME-profile of each compound in drug discovery and development which, at the moment, focuses solely on the patient and largely neglects target bacteria.

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