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

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...

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Published in:	Scientific reports Vol. 8; no. 1; pp. 3939 - 15
Main Authors:	Trofimov, Valentin, Kicka, Sébastien, Mucaria, Sabrina, Hanna, Nabil, Ramon-Olayo, Fernando, Del Peral, Laura Vela-Gonzalez, Lelièvre, Joël, Ballell, Lluís, Scapozza, Leonardo, Besra, Gurdyal S., Cox, Jonathan A. G., Soldati, Thierry
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 02-03-2018 Nature Publishing Group Nature Portfolio
Subjects:	14 14/63 631/154/1435/2417 631/154/555 631/326/421 64 82 Acanthamoeba castellanii - microbiology Animals Antibiotics Antitubercular Agents - pharmacology Bacillus Calmette-Guerin vaccine BCG Biochemistry Cell Line Dictyostelium - microbiology Drug discovery Drug Discovery - methods Drug Resistance, Bacterial - genetics Drugs Genetic engineering Genomes Humanities and Social Sciences Infections Medical treatment Mice Microbial Sensitivity Tests Microglia - cytology Microglia - drug effects multidisciplinary Mutation Mycobacterium marinum Mycobacterium marinum - drug effects Mycobacterium marinum - genetics Mycobacterium marinum - growth & development Pathogens Phagocytes Protozoa Resistant mutant Science Science (multidisciplinary) Tuberculosis Virulence
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-018-22228-6