000222157 001__ 222157
000222157 005__ 20181203024409.0
000222157 0247_ $$2doi$$a10.1016/j.tube.2016.07.011
000222157 022__ $$a1472-9792
000222157 02470 $$2ISI$$a000382201400013
000222157 037__ $$aARTICLE
000222157 245__ $$aMicrococcin P1-A bactericidal thiopeptide active against Mycobacterium tuberculosis
000222157 260__ $$aEdinburgh$$bElsevier$$c2016
000222157 269__ $$a2016
000222157 300__ $$a7
000222157 336__ $$aJournal Articles
000222157 520__ $$aThe lack of proper treatment for serious infectious diseases due to the emergence of multidrug resistance reinforces the need for the discovery of novel antibiotics. This is particularly true for tuberculosis (TB) for which 3.7% of new cases and 20% of previously treated cases are estimated to be caused by multi-drug resistant strains. In addition, in the case of TB, which claimed 1.5 million lives in 2014, the treatment of the least complicated, drug sensitive cases is lengthy and disagreeable. Therefore, new drugs with novel targets are urgently needed to control resistant Mycobacterium tuberculosis strains. In this manuscript we report the characterization of the thiopeptide micrococcin P1 as an anti-tubercular agent. Our biochemical experiments show that this antibiotic inhibits the elongation step of protein synthesis in mycobacteria. We have further identified micrococcin resistant mutations in the ribosomal protein L11 (RplK); the mutations were located in the proline loop at the N-terminus. Reintroduction of the mutations into a clean genetic background, confirmed that they conferred resistance, while introduction of the wild type RplK allele into resistant strains re-established sensitivity. We also identified a mutation in the 23S rRNA gene. These data, in good agreement with previous structural studies suggest that also in M. tuberculosis micrococcin P1 functions by binding to the cleft between the 23S rRNA and the L11 protein loop, thus interfering with the binding of elongation factors Tu and G (EF-Tu and EF-G) and inhibiting protein translocation. (C) 2016 Elsevier Ltd. All rights reserved.
000222157 6531_ $$aTuberculosis
000222157 6531_ $$aDrug development
000222157 6531_ $$aTranslation
000222157 6531_ $$aThiopeptides
000222157 700__ $$aDegiacomi, Giulia$$uUniv Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy
000222157 700__ $$aPersonne, Yoann$$uQueen Mary Univ London, London E1 2AD, England
000222157 700__ $$aMondesert, Guillaume$$uSanofi Aventis R&D, Drug Disposit, F-69367 Lyon, France
000222157 700__ $$aGe, Xueliang$$uUppsala Univ, Dept Cell & Mol Biol, Uppsala, Sweden
000222157 700__ $$aMandava, Chandra Sekhar$$uUppsala Univ, Dept Cell & Mol Biol, Uppsala, Sweden
000222157 700__ $$0244368$$aHartkoorn, Ruben C.$$g183097$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000222157 700__ $$aBoldrin, Francesca$$uUniv Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy
000222157 700__ $$aGoel, Pavitra$$uQueen Mary Univ London, London E1 2AD, England
000222157 700__ $$aPeisker, Kristin$$uUppsala Univ, Dept Cell & Mol Biol, Uppsala, Sweden
000222157 700__ $$0246601$$aBenjak, Andrej$$g229809$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000222157 700__ $$aBarrio, Maria Belen$$uSanofi Aventis R&D, Drug Disposit, F-69367 Lyon, France
000222157 700__ $$aVentura, Marcello$$uUniv Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy
000222157 700__ $$aBrown, Amanda C.$$uQueen Mary Univ London, London E1 2AD, England
000222157 700__ $$aLeblanc, Veronique$$uSanofi Aventis R&D, Drug Disposit, F-69367 Lyon, France
000222157 700__ $$aBauer, Armin$$uSanofi Aventis R&D, Drug Disposit, F-69367 Lyon, France
000222157 700__ $$aSanyal, Suparna$$uUppsala Univ, Dept Cell & Mol Biol, Uppsala, Sweden
000222157 700__ $$0243892$$aCole, Stewart T.$$g177247$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000222157 700__ $$aLagrange, Sophie$$uSanofi Aventis R&D, Drug Disposit, F-69367 Lyon, France
000222157 700__ $$aParish, Tanya$$uQueen Mary Univ London, London E1 2AD, England
000222157 700__ $$aManganelli, Riccardo$$uUniv Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy
000222157 773__ $$j100$$q95-101$$tTuberculosis
000222157 909C0 $$0252302$$pUPCOL$$xU11742
000222157 909CO $$ooai:infoscience.tind.io:222157$$pSV$$particle
000222157 917Z8 $$x217823
000222157 937__ $$aEPFL-ARTICLE-222157
000222157 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000222157 980__ $$aARTICLE