Mycobacterium tuberculosis virulence inhibitors discovered by Mycobacterium marinum high-throughput screening

High-throughput screening facilities do not generally support biosafety level 3 organisms such as Mycobacterium tuberculosis . To discover not only antibacterials, but also virulence inhibitors with either bacterial or host cell targets, an assay monitoring lung fibroblast survival upon infection wa...

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Bibliographic Details
Published in:Scientific reports 2019-01, Vol.9 (1), p.26-26, Article 26
Main Authors: Tükenmez, Hasan, Edström, Isabel, Ummanni, Ramesh, Fick, Stina Berglund, Sundin, Charlotta, Elofsson, Mikael, Larsson, Christer
Format: Article
Language:English
Subjects:
631/154/1435/2163
631/326/22/1290
692/699/255/1856
Anti-Bacterial Agents - isolation & purification
Antimicrobial agents
Biological & chemical terrorism
Biosafety
Cell Survival
Drug discovery
Fibroblasts - physiology
High-throughput screening
High-Throughput Screening Assays - methods
Humanities and Social Sciences
Inhibitors
multidisciplinary
Mycobacterium marinum
Mycobacterium marinum - drug effects
Mycobacterium marinum - pathogenicity
Mycobacterium tuberculosis
Science
Science (multidisciplinary)
Tuberculosis
Virulence
Virulence Factors - antagonists & inhibitors
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Summary:High-throughput screening facilities do not generally support biosafety level 3 organisms such as Mycobacterium tuberculosis . To discover not only antibacterials, but also virulence inhibitors with either bacterial or host cell targets, an assay monitoring lung fibroblast survival upon infection was developed and optimized for 384-plate format and robotic liquid handling. By using Mycobacterium marinum as surrogate organism, 28,000 compounds were screened at biosafety level 2 classification, resulting in 49 primary hits. Exclusion of substances with unfavourable properties and known antimicrobials resulted in 11 validated hits of which 7 had virulence inhibiting properties and one had bactericidal effect also in wild type Mycobacterium tuberculosis . This strategy to discover virulence inhibitors using a model organism in high-throughput screening can be a valuable tool for other researchers working on drug discovery against tuberculosis and other biosafety level 3 infectious agents.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-37176-4