Synthetic EthR inhibitors boost antituberculous activity of ethionamide


The side effects associated with tuberculosis therapy bring with them the risk of noncompliance and subsequent drug resistance. Increasing the therapeutic index of antituberculosis drugs should thus improve treatment effectiveness. Several antituberculosis compounds require in situ metabolic activation to become inhibitory. Various thiocarbamide-containing drugs, including ethionamide, are activated by the mycobacterial monooxygenase EthA, the production of which is controlled by the transcriptional repressor EthR. Here we identify drug-like inhibitors of EthR that boost the bioactivation of ethionamide. Compounds designed and screened for their capacity to inhibit EthR-DNA interaction were co-crystallized with EthR. We exploited the three-dimensional structures of the complexes for the synthesis of improved analogs that boosted the ethionamide potency in culture more than tenfold. In Mycobacterium tuberculosis–infected mice, one of these analogs, BDM31343, enabled a substantially reduced dose of ethionamide to lessen the mycobacterial load as efficiently as the conventional higher-dose treatment. This provides proof of concept that inhibiting EthR improves the therapeutic index of thiocarbamide derivatives, which should prompt reconsideration of their use as first-line drugs.

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Figure 1: Structure of the ligand-binding pocket of EthR.
Figure 2: Sites of BDM14500 interactions with EthR.
Figure 3: Synergistic effect of ethionamide and BDM14500.
Figure 4: Detailed view of the ligand-binding site of EthR co-crystallized with BDM31381.
Figure 5: Comparative measurements of the distance separating the helix-turn-helix DNA-binding motifs (α carbon of Thr60) of EthR upon binding with its ligand.
Figure 6: Ethionamide-boosting effect of BDM31343 on tuberculosis-infected mice.

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We are indebted to G. Mahieu for his invaluable help with the synergistic experiments on M. tuberculosis, P. Rucktooa for crystal structure acquisitions and manipulations, F. Demirkaya for technical support, M. Flipo for support in chemical synthesis, M. Cynamon for sharing experimental data about ethionamide sensitivity in mice and S. Delaroche for data formatting. We thank H. Gras for critical reading of the manuscript and F. Jean, C. Desruelle and V. Dewailly for grants management. Nuclear magnetic resonance spectra acquisitions were done at the Laboratoire d'Application de Résonance Magnétique Nucléaire, Lille. This work was supported by INSERM, Université de Lille 2 Droit et Santé, Institut Pasteur de Lille, CNRS, the Région Nord-Pas de Calais, Ministère délégué à la Recherche et aux Nouvelles Technologies and the European Union (FEDER OBJ2-4.1-2006/3-n°297/9360), l'Agence Nationale de la Recherche, France (ANR-06-EMPB-033). We are indebted to the European Synchrotron Radiation Facility for beam-time allocation (through the Block Allocation Group BAG MX-485) for this project. X.C. is a recipient of a doctoral fellowship from Institut Pasteur de Lille and the Région Nord-Pas de Calais. B.D. is a recipient of a doctoral fellowship of the Ministère de la Recherche. M.A. and V.V. are researchers from the CNRS.

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Correspondence to Alain R Baulard.

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Willand, N., Dirié, B., Carette, X. et al. Synthetic EthR inhibitors boost antituberculous activity of ethionamide. Nat Med 15, 537–544 (2009).

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