Journal Article

Synthetic EthR inhibitors boost antituberculous activity of ethionamide

Déprez-Poulain, Rebecca, Delcroix, Guy, Mathys, Vanessa, Dirié, Bertrand, Locht, Camille, Desroses, Matthieu, Willand, Nicolas, Aumercier, Marc, Singhal, Amit, Carette, Xavier, Déprez, Benoit, Leroux, Florence, Baulard, Alain R, Frénois, Frédéric, Willery, Eve, Bifani, Pablo, Villeret, Vincent

2009

Overview

Several tuberculosis drugs are prodrugs that have to be enzymatically activated during metabolism. Ethionamide is such a drug and is activated by the monooxygenase EthA. EthA is itself regulated by the transcriptional repressor EthR. Here Alain Baulard and his colleagues have designed inhibitors of EthR that boost the antimycobacterial efficacy of ethionamide both in vitro and in vivo . Current therapy with ethionamide requires the use of high doses, often eliciting side effects. Its combination with the EthR repressor should allow lower doses to be used. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Animals / Antibiotics / Antitubercular Agents - therapeutic use / Binding Sites / Biomedical and Life Sciences / Biomedicine / Cancer Research / Causes of / Complications and side effects / Deoxyribonucleic acid / DNA / DNA-Binding Proteins - chemistry / DNA-Binding Proteins - metabolism / Dosage and administration / Drug resistance / Drug Synergism / Drug therapy / Enzyme inhibitors / Ethionamide / Ethionamide - therapeutic use / Genetic aspects / Health aspects / Hydrogen Bonding / Infectious Diseases / Inhibitor drugs / Inhibitors / Life Sciences / Ligands / Metabolic Diseases / Mice / Models, Molecular / Molecular Medicine / Mycobacterium / Neurosciences / Oxadiazoles - therapeutic use / Oxidases / Patient outcomes / Pharmaceutical sciences / Physiological aspects / Prescription drugs / Protein Conformation / Repressor Proteins - antagonists & inhibitors / Repressor Proteins - chemistry / Repressor Proteins - therapeutic use / Side effects / Thiophenes - therapeutic use / Tuberculosis / Tuberculosis - drug therapy