Leads for antitubercular compounds from kinase inhibitor library screens

• Published in: Tuberculosis (Edinburgh, Scotland) Vol. 90; no. 6; pp. 354 - 360
• Main Authors: Magnet, Sophie, Hartkoorn, Ruben C, Székely, Rita, Pató, János, Triccas, James A, Schneider, Patricia, Szántai-Kis, Csaba, Őrfi, László, Chambon, Marc, Banfi, Damiano, Bueno, Manuel, Turcatti, Gerardo, Kéri, György, Cole, Stewart T
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01-11-2010
• Subjects: Antimycobacterial agents; Antitubercular Agents - pharmacology; Corynebacterium glutamicum; DprE1; Gene Library; Humans; Infectious Disease; Kinase inhibitor; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - metabolism; Protein Kinase Inhibitors - metabolism; Protein-Serine-Threonine Kinases - drug effects; Protein-Serine-Threonine Kinases - genetics; Pulmonary/Respiratory; Quinoxaline; Screening; Serine/threonine protein Kinase (STPK); Tuberculosis; Tuberculosis - drug therapy; Tuberculosis - genetics; Tuberculosis - metabolism; DprE1; Screening; Quinoxaline; Tuberculosis; Serine/threonine protein Kinase (STPK); Kinase inhibitor
• ISSN: 1472-9792; 1873-281X
• DOI: 10.1016/j.tube.2010.09.001

Summary Discovering 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 10 μM 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.