Phloretin Exerts Anti-Tuberculosis Activity and Suppresses Lung Inflammation

• Published in: Molecules (Basel, Switzerland) Switzerland), 2017-01, Vol.22 (1), p.183-183
• Main Authors: Jeon, Dasom, Jeong, Min-Cheol, Jnawali, Hum Nath, Kwak, Chulhee, Ryoo, Sungwon, Jung, In Duk, Kim, Yangmee
• Format: Article
• Language: English
• Subjects: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - metabolism; Acyl carrier protein; Acyl carrier protein synthase; Animals; Anti-Inflammatory Agents - pharmacology; antibiotics; Antitubercular Agents - pharmacology; Binding Sites; Biocompatibility; Cell Line; Clinical isolates; Cytokines - secretion; Cytotoxicity; Dendritic cells; Dendritic Cells - drug effects; Drug resistance; Drug Resistance, Multiple, Bacterial; Drugs; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - secretion; Humans; Hydrogen bonding; In vivo methods and tests; Inflammation; Interferon; Interleukin 12; Interleukin 6; Kinases; Lipopolysaccharides; Lung - cytology; Lung - drug effects; Lung - pathology; Lungs; Macrophages - drug effects; MAP kinase; MAP Kinase Signaling System - drug effects; Matrix metalloproteinase; Metalloproteinase; Mice; Mice, Inbred BALB C; mRNA; Mycobacterium; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; natural compound; p38 Mitogen-Activated Protein Kinases - secretion; phloretin; Phloretin - pharmacology; Phosphorylation; Pneumonia - drug therapy; Pneumonia - microbiology; Protein Binding - physiology; Protein kinase; Proteins; Rodents; Tuberculosis; Tumor necrosis factor-TNF; Tumor necrosis factor-α; γ-Interferon
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules22010183

An increase in the prevalence of the drug-resistant necessitates developing new types of anti-tuberculosis drugs. Here, we found that phloretin, a naturally-occurring flavonoid, has anti-mycobacterial effects on H37Rv, multi-drug-, and extensively drug-resistant clinical isolates, with minimum inhibitory concentrations of 182 and 364 μM, respectively. Since cause lung inflammation that contributes to tuberculosis pathogenesis, anti-inflammatory effects of phloretin in interferon-γ-stimulated MRC-5 human lung fibroblasts and lipopolysaccharide (LPS)-stimulated dendritic cells were investigated. The release of interleukin (IL)-1β, IL-12, and tumor necrosis factor (TNF)-α was inhibited by phloretin. The mRNA levels of IL-1β, IL-6, IL-12, TNF-α, and matrix metalloproteinase-1, as well as p38 mitogen-activated protein kinase and extracellular signal-regulated kinase phosphorylation, were suppressed. A mouse in vivo study of LPS-stimulated lung inflammation showed that phloretin effectively suppressed the levels of TNF-α, IL-1β, and IL-6 in lung tissue with low cytotoxicity. Phloretin was found to bind β-ketoacyl acyl carrier protein synthase III (mtKASIII) with high affinity (7.221 × 10⁷ M ); a binding model showed hydrogen bonding of A-ring 2'-hydroxy and B-ring 4-hydroxy groups of phloretin with Asn261 and Cys122 of mtKASIII, implying that mtKASIII can be a potential target protein. Therefore, phloretin can be a useful dietary natural product with anti-tuberculosis benefits.