Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets

Article Article scientifique Article Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets eng 2018 author Trofimov Valentin 709788 author Kicka Sébastien 736074 author Mucaria Sabrina 756516 author Hanna Nabil 856070 author Ramon-Olayo Fernando author Del Peral Laura Vela-Gonzalez author Lelièvre Joël author Ballell Lluís author Scapozza Leonardo 600318 author Besra Gurdyal S author Cox Jonathan A G author Soldati Thierry 0000-0002-2056-7931 135632 3939 10.1038/s41598-018-22228-6 29500372 2045-2322 Tuberculosis remains a serious threat to human health world-wide, and improved efficiency of medical treatment requires a better understanding of the pathogenesis and the discovery of new drugs. In the present study, we performed a whole-cell based screen in order to complete the characterization of 168 compounds from the GlaxoSmithKline TB-set. We have established and utilized novel previously unexplored host-model systems to characterize the GSK compounds, i.e. the amoeboid organisms D. discoideum and A. castellanii, as well as a microglial phagocytic cell line, BV2. We infected these host cells with Mycobacterium marinum to monitor and characterize the anti-infective activity of the compounds with quantitative fluorescence measurements and high-content microscopy. In summary, 88.1% of the compounds were confirmed as antibiotics against M. marinum, 11.3% and 4.8% displayed strong anti-infective activity in, respectively, the mammalian and protozoan infection models. Additionally, in the two systems, 13-14% of the compounds displayed pro-infective activity. Our studies underline the relevance of using evolutionarily distant pathogen and host models in order to reveal conserved mechanisms of virulence and defence, respectively, which are potential "universal" targets for intervention. Subsequent mechanism of action studies based on generation of over-expresser M. bovis BCG strains, generation of spontaneous resistant mutants and whole genome sequencing revealed four new molecular targets, including FbpA, MurC, MmpL3 and GlpK. Dewey 540 Dewey 615 39 Département de biochimie 144 31 Section des sciences pharmaceutiques 17 false Scientific Reports 8 1 82004d4f-65f9-4905-864e-7d2049af8787 Article (Published version) Public Trofimov_et_al18.pdf 3681698 application/pdf OA OTHER openAccess Faculté des sciences / Section de chimie et biochimie / Département de biochimie Faculté des sciences / Section des sciences pharmaceutiques

Title	Published in	Year	Views	Downloads

Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets	Scientific Reports	2018	559	219
Étude et sélection de molécules antituberculeuses pour la réalisation dʼune étude de relation structure-activité (SAR)		2014	260	3

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