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Targeting Lsr2/DNA complexation for dysregulation of gene expression in Mycobacterium Tuberculosis
Author(s) -
Pinault Lucile,
Han JeongSun,
Kang Choongmin,
Franco Jimmy,
Ronning Donald R.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.806.1
Subject(s) - mycobacterium smegmatis , mycobacterium tuberculosis , biology , dna , gene , mycobacterium , microbiology and biotechnology , tuberculosis , repressor , genome , promoter , transcription factor , genetics , gene expression , bacteria , medicine , pathology
The identification of new drug targets and mechanisms of action against tuberculosis has become urgent, as the emergence of drug‐resistant strains has made many treatments ineffective. Lsr2 is a protein encoded by the Mycobacterium tuberculosis genome that acts as a global repressor of transcription by binding AT‐rich promoter regions of the mycobacterial DNA. Inhibiting this function could potentially dysregulate a wide array of genes, as Lsr2 binds about 20% of the Mycobacterium tuberculosis genome. Described here are experiments demonstrating that Zafirlukast is able to disrupt the Lsr2/DNA complex. This ability was shown in vitro using a fluorescence polarization assay. This compound also exhibits growth inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis on a Kirby Bauer assay but shows no activity against Escherichia coli . Transcription levels of genes shown to be bound by Lsr2 have been monitored in vivo after applying the drug to a culture of Mycobacterium tuberculosis and the results suggest that Zafirlukast promotes dysregulation of mycobacterial transcription. This drug is already commercially available and is commonly used as a treatment for asthma. As its mechanism of action appears to be distinct from current drugs against tuberculosis, it offers a new potential lead for the treatment of this disease.