Abstract
Mycobacterium tuberculosis is a global pathogen of huge importance which can adapt to several host niche environments in which carbon source availability is likely to vary. We developed and ran a phenotypic screen using butyrate as the sole carbon source to be more reflective of the host lung environment. We screened a library of ∼87,000 small compounds and identified compounds which demonstrated good antitubercular activity against M. tuberculosis grown with butyrate but not with glucose as the carbon source. Among the hits, we identified an oxadiazole series (six compounds) which had specific activity against M. tuberculosis but which lacked cytotoxicity against mammalian cells.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
MeSH terms
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Animals
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Antitubercular Agents / chemistry
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Antitubercular Agents / pharmacology*
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Butyric Acid / metabolism*
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Cell Survival / drug effects
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Chlorocebus aethiops
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Culture Media / chemistry
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Culture Media / metabolism*
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Glucose / metabolism
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High-Throughput Screening Assays
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Isoniazid / pharmacology
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Kanamycin / pharmacology
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Levofloxacin / pharmacology
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Metabolic Networks and Pathways / physiology
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Microbial Sensitivity Tests
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / growth & development
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Mycobacterium tuberculosis / metabolism
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology*
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Species Specificity
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Structure-Activity Relationship
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Vero Cells
Substances
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Antitubercular Agents
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Culture Media
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Oxadiazoles
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Small Molecule Libraries
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Butyric Acid
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Kanamycin
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Levofloxacin
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Glucose
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Isoniazid
Grants and funding
The work at IDRI was funded in part by Eli Lilly and Company in support of the mission of the Lilly TB Drug Discovery Initiative and with funding from the Bill and Melinda Gates Foundation under grant no. OPP1024038.