Contributors: Institut de pharmacologie et de biologie structurale (IPBS); Université Toulouse III - Paul Sabatier (UT3); Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS); Tuberculose et biologie des infections [IPBS, Toulouse]; Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3); Pathogénomique mycobactérienne intégrée; Institut Pasteur [Paris] (IP); This study was supported by grants from the European Union (LSHP‐CT‐2005‐018923 and 260872), the EU‐EFPIA Innovative Medicines Initiative (grant agreement 115337), the Agence Nationale de la Recherche (FASMY, grant ANR‐14‐CE16‐0012). RB acknowledges support by the Fondation pour la Recherche Médicale (DEQ20130326471).; We wish to thank Lucie Spina and Dr. Emilie Huc for their help during some MS analyses, Wladimir Malaga for the generous gift of modified versions of plasmids pMV361 and pJV53, Fabien Le Chevalier for help with bacterial staining and Dr. Marie‐Antoinette Lanéelle for helpful discussions. The NMR data were collected on the PICT‐IbiSA facility; NMR experiments were performed on the PICT‐Genotoul platform of Toulouse funded by CNRS, Université de Toulouse‐UPS, Ibisa, European structural funds and the Midi‐Pyrénées region.; ANR-14-CE16-0012,FASMY,Une étude intégrée du système Fatty acid Synthase de type II mycobactérien, une cible stratégique pour de nouveaux médicaments antituberculeux.(2014); Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3); Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées; Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3); Institut Pasteur [Paris]
نبذة مختصرة : SummaryUnderstanding the molecular strategies used by Mycobacterium tuberculosis to invade and persist within the host is of paramount importance to tackle the tuberculosis pandemic. Comparative genomic surveys have revealed that hadC, encoding a subunit of the HadBC dehydratase, is mutated in the avirulent M. tuberculosis H37Ra strain. We show here that mutation or deletion of hadC affects the biosynthesis of oxygenated mycolic acids, substantially reducing their production level. Additionally, it causes the loss of atypical extra‐long mycolic acids, demonstrating the involvement of HadBC in the late elongation steps of mycolic acid biosynthesis. These events have an impact on the morphotype, cording capacity and biofilm growth of the bacilli as well as on their sensitivity to agents such as rifampicin. Furthermore, deletion of hadC leads to a dramatic loss of virulence: an almost 4‐log drop of the bacterial load in the lungs and spleens of infected immunodeficient mice. Both its unique function and importance for M. tuberculosis virulence make HadBC an attractive therapeutic target for tuberculosis drug development.
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