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) H37Rv, 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′,4′‐tetrahydroxyflavone (3,6,3′,4′‐THF) activities revealed that 3,6,3′,4′‐THF did not have anti‐tuberculosis (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 signal‐regulated 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.