title: Oxadiazoles Have Butyrate-Specific Conditional Activity against Mycobacterium tuberculosis.
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.
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Julie V
authors.initials: JV
authors.lastname: Early
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Casey
authors.affiliation: Eli Lilly and Company, Alcobendas, Madrid, Spain.
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Martinez-Grau
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Gonzalez Valcarcel
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Vieth
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Juliane
authors.initials: J
authors.lastname: Ollinger
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Mai Ann
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Torey
authors.initials: T
authors.lastname: Alling
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Files
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Ovechkina
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, USA tanya.parish@idri.org.
authors.forename: Tanya
authors.initials: T
authors.lastname: Parish
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D020148:Butyric Acid / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003470:Culture Media / Q000737:chemistry / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D057166:High-Throughput Screening Assays; D007538:Isoniazid / Q000494:pharmacology; D007612:Kanamycin / Q000494:pharmacology; D064704:Levofloxacin / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D003470:Culture Media; D010069:Oxadiazoles; D054852:Small Molecule Libraries; D020148:Butyric Acid; D007612:Kanamycin; D064704:Levofloxacin; D005947:Glucose; D007538:Isoniazid