Phloretin Exerts Anti-Tuberculosis Activity and Suppresses Lung Inflammation.

ABSTRACT: An increase in the prevalence of the drug-resistant Mycobacteria tuberculosis 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 ?M, respectively. Since Mycobacteria cause lung inflammation that contributes to tuberculosis pathogenesis, anti-inflammatory effects of phloretin in interferon-?-stimulated MRC-5 human lung fibroblasts and lipopolysaccharide (LPS)-stimulated dendritic cells were investigated. The release of interleukin (IL)-1?, IL-12, and tumor necrosis factor (TNF)-? was inhibited by phloretin. The mRNA levels of IL-1?, IL-6, IL-12, TNF-?, 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-?, IL-1?, and IL-6 in lung tissue with low cytotoxicity. Phloretin was found to bind M. tuberculosis ?-ketoacyl acyl carrier protein synthase III (mtKASIII) with high affinity (7.221 × 10? 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.

SUBMITTER: Jeon D 

PROVIDER: S-EPMC6155841 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature