3,6‐Dihydroxyflavone Has Antituberculosis Activity and Suppresses Lung Inflammation

Abstract

The antimycobacterial and anti-inflammatory effects of 3,6-dihydroxyflavone (3,6-DHF), a flavonoid with anticancer and antibacterial activities, were investigated in lipopolysaccharide (LPS)-stimulated human lung fibroblast MRC-5 cells. 3,6-DHF had antimycobacterial effects on Mycobacterium tuberculosis (Mtb) H 37 Rv, multidrug-resistant, and extensively drug-resistant clinical isolates with mean minimum inhibitory concentrations of 25, 100, and 100 μg/mL, respectively. 3,6-DHF bound Mtb β-ketoacyl-acyl carrier protein synthase III (mtKASIII) with high affinity through hydrogen bonding of 3,6-DHF of A-ring 6-hydroxyl and C-ring 3-hydroxyl groups with Tyr304 and Gly209 of mtKASIII. Comparison of 3,6-DHF and 3,6,3 0 ,4 0 -tetrahydroxyflavone (3,6,3 0 ,4 0 -THF) activities revealed that 3,6,3 0 ,4 0 -THF did not have antituberculosis (TB) activity, implying that increased hydrophilicity decreases TB membrane permeabilization. 3,6-DHF reduced tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12, IL-1β, and matrix metalloproteinase (MMP)-1 mRNA levels and suppressed phosphorylation levels of extracellular signalregulated kinase (ERK) in LPS-stimulated MRC-5 cells. These data indicate that 3,6-DHF could be developed as a potential anti-TB drug, which also suppresses lung inflammation.