Magnet, SophieHartkoorn, Ruben C.Székely, RitaPató, JánosTriccas, James A.Schneider, PatriciaSzántai-Kis, CsabaOrfi, LászlóChambon, MarcBanfi, DamianoBueno, ManuelTurcatti, GerardoKéri, GyörgyCole, Stewart T.2010-11-082010-11-082010-11-08201010.1016/j.tube.2010.09.001https://infoscience.epfl.ch/handle/20.500.14299/57258WOS:000283739000005Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find antimycobacterial scaffolds, we screened a kinase inhibitor library of more than 12,000 compounds using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and a target-based assay with the protein kinase PknA. Seventeen "hits" came from the whole cell-based screening approach, from which three displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10μM and were non-mutagenic and non-cytotoxic. Two of these hits were specific for M. tuberculosis versus C. glutamicum and none of them was found to inhibit the essential serine/threonine protein kinases, PknA and PknB present in both bacteria. One of the most active hits, VI-18469, had a benzoquinoxaline pharmacophore while another, VI-9376, is structurally related to a new class of antimycobacterial agents, the benzothiazinones (BTZ). Like the BTZ, VI-9376 was shown to act on the essential enzyme decaprenylphosphoryl-β-D-ribose 2'-epimerase, DprE1, required for arabinan synthesis.TuberculosisScreeningKinase inhibitorQuinoxalineSerine/threonine protein Kinase (STPK)DprE1Mycobacterium-TuberculosisPathogenic MycobacteriaProtein-KinasesDrug DiscoveryPknbIdentificationMacrophagesClofazimineCandidateResistanttext::journal::journal article::research article