UNIGE document Scientific Article
previous document  unige:103009  next document
add to browser collection
Title

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

Authors
Ramon-Olayo, Fernando
Del Peral, Laura Vela-Gonzalez
Lelièvre, Joël
Ballell, Lluís
show hidden authors show all authors [1 - 12]
Published in Scientific Reports. 2018, vol. 8, no. 1, p. 3939
Abstract 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.
Identifiers
PMID: 29500372
Full text
Article (Published version) (3.5 MB) - public document Free access
Structures
Citation
(ISO format)
TROFIMOV, Valentin et al. Antimycobacterial drug discovery using Mycobacteria-infected amoebae identifies anti-infectives and new molecular targets. In: Scientific Reports, 2018, vol. 8, n° 1, p. 3939. https://archive-ouverte.unige.ch/unige:103009

44 hits

7 downloads

Update

Deposited on : 2018-03-19

Export document
Format :
Citation style :