Re-exploring the salicylanilide scaffold for the inhibition of mycolic acid synthesis in Mycobacterium tuberculosis
Résumé
Tuberculosis (TB) remains a global health crisis, further exacerbated by the slow pace of progress in developing new treatment options, and the emergence of extreme and total drug resistance to existing drugs. Infection cases keep increasing yearly, with a global number of 7.5 million of people diagnosed in 2022. As for other bacterial bugs, the most pressing challenge lies in the urgent need of finding new active compounds, acting through novel modes of action to tackle resistances. A unique feature of Mycobacterium tuberculosis (Mtb), the causative agent of TB, is its complex and lipid-rich cell envelope. Therefore, targeting the biosynthesis pathway of cell envelope mycolic acids is a historical strategy against Mycobacterium tuberculosis, yet the enzyme FadD32 is still an underexplored although highly relevant (and druggable) target. We have previously developed a miniaturized automatized enzymatic assay, which allowed the high-throughput screening of a drug repurposing library containing 1280 approved human or veterinary drugs (Prestwick Chemical Library). We obtained 36 hits that we further validated for their phenotypic activity on M. tuberculosis (MIC 0.08 – 10 µM). This led to identification of one promising pharmacophore, presenting a salicylanilide scaffold that we are now studying further by synthesizing and evaluating derivatives. Exploring SARs, we develop a hit to a lead medicinal chemistry project, searching for a novel anti-tubercular candidate targeting FadD32. The preliminary results of this approach will be presented.
Domaines
ChimieOrigine | Fichiers produits par l'(les) auteur(s) |
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