Leads for antitubercular compounds from kinase inhibitor library screens
| Autor: | Sophie Magnet, Damiano Banfi, László Őrfi, Patricia Schneider, Csaba Szántai-Kis, James A. Triccas, Ruben C. Hartkoorn, Gerardo Turcatti, Stewart T. Cole, György Kéri, Manuel Bueno, János Pató, Rita Székely, Marc Chambon |
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| Rok vydání: | 2010 |
| Předmět: |
Microbiology (medical)
Identification Quinoxaline medicine.drug_class Serine/threonine protein Kinase (STPK) Immunology Antitubercular Agents DprE1 Protein Serine-Threonine Kinases Biology Antimycobacterial Clofazimine Candidate Microbiology Corynebacterium glutamicum Mycobacterium tuberculosis Drug Discovery Pathogenic Mycobacteria medicine Humans Tuberculosis Protein kinase A Protein Kinase Inhibitors Gene Library Kinase inhibitor Drug discovery Kinase Macrophages biology.organism_classification Resistant Pknb Multiple drug resistance Infectious Diseases Biochemistry Mycobacterium-Tuberculosis Screening Protein-Kinases Pharmacophore |
| Zdroj: | Tuberculosis. 90:354-360 |
| ISSN: | 1472-9792 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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