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 μM, respectively. Since Mycobacteria 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 M. tuberculosis β-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.

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

“…This has caused a decrease of the efficacy of TB drug therapies. 32 The efficacy of phloretin is due to the flexible open structure that allows it to permeabilize the Mtb membrane. 35 Drugs currently available to treat TB, such as isoniazid, rifampicin, and kanamycin, have serious adverse effects including hepatitis, skin rashes, nausea, vomiting, abdominal pain, thrombocytopenic purpura, auditory nerve damage, vertigo, and nephrotoxicity.…”

“…The virulence of Mtb has recently increased and TB has become one of the most serious infections worldwide. 32 The relationship between isoform structures and anti-TB effects has been investigated, and hydrophobicity is an important physiochemical property that affects the efficacy of drug molecule, too. Even though the efficacy of plant flavonoids such as myricetin, kaempferol, and quercetin as antimycobacterial, antiparasitic, and antiseptic drugs is relatively weak compared to these drugs but they do not show any adverse effects.…”

“…21,28 Sodium lauryl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) was conducted using 30 μg of protein per well. Detailed expression and purification method were described previously 32 Fluorescence Quenching Between mtKASIII and 3,6-DHF. The membrane was blocked for 1 h at room temperature using 3% skim milk in TBST buffer (25 mM Tris, 140 mM NaCl, 3 mM KCl, and 0.1% Tween20) and incubated overnight at 4 C with specific antibodies.…”

The War against Tuberculosis: A Review of Natural Compounds and Their Derivatives

“…Flavonoids are polyphenolic compounds that can be found in fruits, vegetables, legumes, nuts and plant-derived foods (including coffee and red wine) [87]. In previous work, the polyphenolic compound phloretin, a dietary flavone found in apples (M. domestica) was discovered to have many biological functions, including possible antineoplastic and anti-inflammatory effects (such as production of chemokines, cytokines and other factors induced by leukocytes) [87]. Investigators conducted experiments to determine if phloretin also had antimicrobial effects on various strains of TB (H37Rv, MDR-TB and XDR-TB).…”

Special Issue “Structure–Activity Relationship of Natural Products”

“…Echeverría, J. et al [ 1 ] focus on the antibacterial properties of natural (plant-derived) flavones and flavanones. The potential of the natural flavonoid phloretin as an antimycobacterial agent (anti-tuberculosis), as well as an anti-inflammatory compound, was also investigated by Jeon and collaborators [ 2 ]. The capacity of the natural plant, pterostilbene, and its derivatives to act as anti-biofilm agents against Candida albicans was described by Hu et al [ 3 ].…”