Êtes-vous un étudiant de l'EPFL à la recherche d'un projet de semestre?
Travaillez avec nous sur des projets en science des données et en visualisation, et déployez votre projet sous forme d'application sur GraphSearch.
4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-beta-D-ribose 2'-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of similar to 100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure-activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.
Chargement
Chargement
Chargement
Chargement
Chargement
Stewart Cole, Joao Pedro De Almeida Neres, Anirban Ghosh, Florence Pojer
Stewart Cole, Joao Pedro De Almeida Neres, Neeraj Dhar, Ruben Hartkoorn, Gaëlle Séraphine Kolly, Florence Pojer
Luciano Andres Abriata, Stewart Cole, Matteo Dal Peraro, Gaëlle Séraphine Kolly, Raju Mukherjee, Mahé Cécile Raccaud, Claudia Sala