title: Zafirlukast inhibits complexation of Lsr2 with DNA and growth of Mycobacterium tuberculosis.
abstract: The mycobacterial nucleoid-associated protein Lsr2 is a DNA-bridging protein that plays a role in condensation and structural organization of the genome and acts as a global repressor of gene transcription. Here we describe experiments demonstrating that zafirlukast inhibits the complexation between Lsr2 and DNA in vitro. Zafirlukast is shown to inhibit growth in two different species of mycobacteria tested but exhibits no growth inhibition of Escherichia coli. The Lsr2 inhibitory activity is reflected in vivo as determined by monitoring of transcription levels in Mycobacterium tuberculosis. These data suggest that zafirlukast inhibits Lsr2 function in vivo, promoting dysregulation of the expression of an array of genes typically bound by Lsr2 and hindering growth. Since zafirlukast likely operates by a mechanism distinct from current M. tuberculosis drugs and is currently used as a prophylactic treatment for asthma, it offers an intriguing lead for development of new treatments for tuberculosis.
authors: Department of Chemistry, University of Toledo, Toledo, Ohio, USA.
authors: Lucile
authors: L
authors: Pinault
authors: Jeong-Sun
authors: JS
authors: Han
authors: Choong-Min
authors: CM
authors: Kang
authors: Jimmy
authors: J
authors: Franco
authors: Donald R
authors: DR
authors: Ronning
mesh_terms: D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000995:Antitubercular Agents / Q000494:pharmacology*; D004269:DNA, Bacterial / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058492:Drug Repositioning; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D007211:Indoles; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D048448:Phenylcarbamates; D011485:Protein Binding; D013045:Species Specificity; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018927:Anti-Asthmatic Agents; D000995:Antitubercular Agents; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D007211:Indoles; C539619:Lsr2 protein, Mycobacterium tuberculosis; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds; C062735:zafirlukast