title: Phloretin Exerts Anti-Tuberculosis Activity and Suppresses Lung Inflammation.
abstract: An increase in the prevalence of the drug-resistantMycobacteria tuberculosisnecessitates 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. SinceMycobacteriacause 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 bindM. tuberculosisβ-ketoacyl acyl carrier protein synthase III (mtKASIII) with high affinity (7.221 × 10⁷ M-1); 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.
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea. dasom921012@konkuk.ac.kr.
authors.forename: Dasom
authors.initials: D
authors.lastname: Jeon
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea. boby8520@konkuk.ac.kr.
authors.forename: Min-Cheol
authors.initials: MC
authors.lastname: Jeong
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea. humnath@konkuk.ac.kr.
authors.forename: Hum Nath
authors.initials: HN
authors.lastname: Jnawali
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea. chk90@konkuk.ac.kr.
authors.forename: Chulhee
authors.initials: C
authors.lastname: Kwak
authors.affiliation: Korean National Tuberculosis Association, Seoul 06763, Korea. viweon@naver.com.
authors.forename: Sungwon
authors.initials: S
authors.lastname: Ryoo
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Seoul 05029, Korea. jungid@kku.ac.kr.
authors.forename: In Duk
authors.initials: ID
authors.lastname: Jung
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea. ymkim@konkuk.ac.kr.
authors.forename: Yangmee
authors.initials: Y
authors.lastname: Kim
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects; D024901:Drug Resistance, Multiple, Bacterial; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010693:Phloretin / Q000494:pharmacology*; D011014:Pneumonia / Q000188:drug therapy* / Q000382:microbiology; D011485:Protein Binding / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000995:Antitubercular Agents; D016207:Cytokines; D008070:Lipopolysaccharides; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010693:Phloretin
keywords: Mycobacterium tuberculosis; antibiotics; inflammation; natural compound; phloretin