<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Willand,N.</style></author><author><style face="normal" font="default" size="100%">Dirie,B.</style></author><author><style face="normal" font="default" size="100%">Carette,X.</style></author><author><style face="normal" font="default" size="100%">Bifani,P.</style></author><author><style face="normal" font="default" size="100%">Singhal,A.</style></author><author><style face="normal" font="default" size="100%">Desroses,M.</style></author><author><style face="normal" font="default" size="100%">Leroux,F.</style></author><author><style face="normal" font="default" size="100%">Willery,E.</style></author><author><style face="normal" font="default" size="100%">Vanessa Mathys</style></author><author><style face="normal" font="default" size="100%">Deprez-Poulain,R.</style></author><author><style face="normal" font="default" size="100%">Delcroix,G.</style></author><author><style face="normal" font="default" size="100%">Frenois,F.</style></author><author><style face="normal" font="default" size="100%">Aumercier,M.</style></author><author><style face="normal" font="default" size="100%">Locht,C.</style></author><author><style face="normal" font="default" size="100%">Villeret,V.</style></author><author><style face="normal" font="default" size="100%">Deprez,B.</style></author><author><style face="normal" font="default" size="100%">Baulard,A.R.</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Synthetic EthR inhibitors boost antituberculous activity of ethionamide36849</style></title><secondary-title><style face="normal" font="default" size="100%">Nat.Med.</style></secondary-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">0</style></keyword><keyword><style  face="normal" font="default" size="100%">a</style></keyword><keyword><style  face="normal" font="default" size="100%">Activity</style></keyword><keyword><style  face="normal" font="default" size="100%">Agent</style></keyword><keyword><style  face="normal" font="default" size="100%">Agents</style></keyword><keyword><style  face="normal" font="default" size="100%">Animals</style></keyword><keyword><style  face="normal" font="default" size="100%">antagonists &amp; inhibitors</style></keyword><keyword><style  face="normal" font="default" size="100%">Antitubercular Agents</style></keyword><keyword><style  face="normal" font="default" size="100%">article</style></keyword><keyword><style  face="normal" font="default" size="100%">AS</style></keyword><keyword><style  face="normal" font="default" size="100%">Binding Sites</style></keyword><keyword><style  face="normal" font="default" size="100%">chemistry</style></keyword><keyword><style  face="normal" font="default" size="100%">concept</style></keyword><keyword><style  face="normal" font="default" size="100%">conventional</style></keyword><keyword><style  face="normal" font="default" size="100%">culture</style></keyword><keyword><style  face="normal" font="default" size="100%">de</style></keyword><keyword><style  face="normal" font="default" size="100%">DNA-Binding Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">DRUG</style></keyword><keyword><style  face="normal" font="default" size="100%">Drug Resistance</style></keyword><keyword><style  face="normal" font="default" size="100%">Drug Synergism</style></keyword><keyword><style  face="normal" font="default" size="100%">drug therapy</style></keyword><keyword><style  face="normal" font="default" size="100%">drugs</style></keyword><keyword><style  face="normal" font="default" size="100%">effect</style></keyword><keyword><style  face="normal" font="default" size="100%">effects</style></keyword><keyword><style  face="normal" font="default" size="100%">electronic</style></keyword><keyword><style  face="normal" font="default" size="100%">ET</style></keyword><keyword><style  face="normal" font="default" size="100%">Ethionamide</style></keyword><keyword><style  face="normal" font="default" size="100%">France</style></keyword><keyword><style  face="normal" font="default" size="100%">Hydrogen Bonding</style></keyword><keyword><style  face="normal" font="default" size="100%">identify</style></keyword><keyword><style  face="normal" font="default" size="100%">im</style></keyword><keyword><style  face="normal" font="default" size="100%">improve</style></keyword><keyword><style  face="normal" font="default" size="100%">index</style></keyword><keyword><style  face="normal" font="default" size="100%">interaction</style></keyword><keyword><style  face="normal" font="default" size="100%">IS</style></keyword><keyword><style  face="normal" font="default" size="100%">journal</style></keyword><keyword><style  face="normal" font="default" size="100%">Ligands</style></keyword><keyword><style  face="normal" font="default" size="100%">metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">mice</style></keyword><keyword><style  face="normal" font="default" size="100%">Models,Molecular</style></keyword><keyword><style  face="normal" font="default" size="100%">Mycobacterium</style></keyword><keyword><style  face="normal" font="default" size="100%">Mycobacterium tuberculosis</style></keyword><keyword><style  face="normal" font="default" size="100%">national</style></keyword><keyword><style  face="normal" font="default" size="100%">Oxadiazoles</style></keyword><keyword><style  face="normal" font="default" size="100%">production</style></keyword><keyword><style  face="normal" font="default" size="100%">protein</style></keyword><keyword><style  face="normal" font="default" size="100%">Protein Conformation</style></keyword><keyword><style  face="normal" font="default" size="100%">Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Repressor Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Research</style></keyword><keyword><style  face="normal" font="default" size="100%">Research Support</style></keyword><keyword><style  face="normal" font="default" size="100%">resistance</style></keyword><keyword><style  face="normal" font="default" size="100%">risk</style></keyword><keyword><style  face="normal" font="default" size="100%">SB - IM</style></keyword><keyword><style  face="normal" font="default" size="100%">Side effects</style></keyword><keyword><style  face="normal" font="default" size="100%">Side-effects</style></keyword><keyword><style  face="normal" font="default" size="100%">structure</style></keyword><keyword><style  face="normal" font="default" size="100%">Synthetic</style></keyword><keyword><style  face="normal" font="default" size="100%">therapeutic use</style></keyword><keyword><style  face="normal" font="default" size="100%">Therapy</style></keyword><keyword><style  face="normal" font="default" size="100%">Thiophenes</style></keyword><keyword><style  face="normal" font="default" size="100%">treatment</style></keyword><keyword><style  face="normal" font="default" size="100%">Tuberculosis</style></keyword><keyword><style  face="normal" font="default" size="100%">use</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2009</style></year><pub-dates><date><style  face="normal" font="default" size="100%">0/5/2009</style></date></pub-dates></dates><number><style face="normal" font="default" size="100%">544</style></number><volume><style face="normal" font="default" size="100%">15</style></volume><pages><style face="normal" font="default" size="100%">537 - 544</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">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</style></abstract><issue><style face="normal" font="default" size="100%">5</style></issue><custom1><style face="normal" font="default" size="100%">38473</style></custom1><section><style face="normal" font="default" size="100%">537</style></section></record></records></xml>