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ACS Chem Biol. 2015 Mar 20;10(3):705-14. doi: 10.1021/cb5007163. Epub 2014 Dec 9.

2-Carboxyquinoxalines kill mycobacterium tuberculosis through noncovalent inhibition of DprE1.

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†More Medicines for Tuberculosis (MM4TB) Consortium (
‡Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
§Department of Biology and Biotecnology "Lazzaro Spallanzani", University of Pavia, 27100 Pavia, Italy.
∥Tydock Pharma, srl Via Campi 183, 41125 Modena, Italy.
⊥Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 183, 41126 Modena, Italy.
#A. N. Bakh Institute of Biochemistry, Russian Academy of Science, 119071 Moscow, Russia.
∇Inserm U1019 - CNRS UMR 8204, Institut Pasteur de Lille, Université de Lille, 1 rue du Professeur Calmette, 59019, Lille, France.
○Department of Chemistry and Pharmacy, University of Sassari, 07100 Sassari, Italy.
◆Department of Chemistry, University of Pavia, 27100 Pavia, Italy.


Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 μM, Ty38c is bactericidal and active against intracellular bacteria. To investigate its mechanism of action, we isolated mutants resistant to Ty38c and sequenced their genomes. Mutations were found in rv3405c, coding for the transcriptional repressor of the divergently expressed rv3406 gene. Biochemical studies clearly showed that Rv3406 decarboxylates Ty38c into its inactive keto metabolite. The actual target was then identified by isolating Ty38c-resistant mutants of an M. tuberculosis strain lacking rv3406. Here, mutations were found in dprE1, encoding the decaprenylphosphoryl-d-ribose oxidase DprE1, essential for biogenesis of the mycobacterial cell wall. Genetics, biochemical validation, and X-ray crystallography revealed Ty38c to be a noncovalent, noncompetitive DprE1 inhibitor. Structure-activity relationship studies generated a family of DprE1 inhibitors with a range of IC50's and bactericidal activity. Co-crystal structures of DprE1 in complex with eight different quinoxaline analogs provided a high-resolution interaction map of the active site of this extremely vulnerable target in M. tuberculosis.

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