Tomatidine

Unraveling the structure-activity relationship of tomatidine, a steroid alkaloid with unique antibiotic properties against persistent forms of Staphylococcus aureus.[Pubmed: 24877760]

Eur J Med Chem. 2014 Jun 10;80:605-20.

Staphylococcus aureus (S. aureus) is responsible for difficult-to-treat and relapsing infections and constitutes one of the most problematic pathogens due to its multiple resistances to clinically available antibiotics. Additionally, the ability of S. aureus to develop small-colony variants is associated with a reduced susceptibility to aminoglycoside antibiotics and in vivo persistence.
METHODS AND RESULTS:
We have recently demonstrated that Tomatidine, a steroid alkaloid isolated from tomato plants, possesses anti-virulence activity against normal strains of S. aureus as well as the ability to potentiate the effect of aminoglycoside antibiotics. In addition, Tomatidine has shown antibiotic activity against small-colony variants of S. aureus.
CONCLUSIONS:
We herein report the first study of the structure-activity relationship of Tomatidine against S. aureus.

Tomatidine inhibits invasion of human lung adenocarcinoma cell A549 by reducing matrix metalloproteinases expression.[Pubmed: 23566884]

Chem Biol Interact. 2013 May 25;203(3):580-7.

Tomatidine is an aglycone of glycoalkaloid tomatine in tomato. Tomatidine is found to possess anti-inflammatory properties and may serve as a chemosensitizer in multidrug-resistant tumor cells. However, the effect of Tomatidine on cancer cell metastasis remains unclear.
METHODS AND RESULTS:
This study examines the effect of Tomatidine on the migration and invasion of human lung adenocarcinoma A549 cell in vitro. The data demonstrates that Tomatidine does not effectively inhibit the viability of A549 cells. When treated with non-toxic doses of Tomatidine, cell invasion is markedly suppressed by Boyden chamber invasion assay, while cell migration is not affected. Tomatidine reduces the mRNA level of matrix metalloproteinase-2 (MMP-2), MMP-9 and increases the expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK), as well as tissue inhibitor of metalloproteinase-1 (TIMP-1). The immunoblotting assays indicate that Tomatidine is very effective in suppressing the phosphorylation of Akt and extracellular signal regulating kinase (ERK). In addition, Tomatidine significantly decreases the nuclear level of nuclear factor kappa B (NF-κB), which suggests that Tomatidine inhibits NF-κB activity. Furthermore, the treatment of inhibitors specific for PI3K/Akt (LY294002), ERK (U0126), or NF-κB (pyrrolidine dithiocarbamate) to A549 cells reduced cell invasion and MMP-2/9 expression.
CONCLUSIONS:
The results suggest that Tomatidine inhibits the invasion of A549 cells by reducing the expression of MMPs. It also inhibits ERK and Akt signaling pathways and NF-κB activity. These findings demonstrate a new therapeutic potential for Tomatidine in anti-metastatic therapy.

Tomatidine inhibits replication of Staphylococcus aureus small-colony variants in cystic fibrosis airway epithelial cells.[Pubmed: 21357296]

Antimicrob Agents Chemother. 2011 May;55(5):1937-45.

Small-colony variants (SCVs) often are associated with chronic Staphylococcus aureus infections, such as those encountered by cystic fibrosis (CF) patients.
METHODS AND RESULTS:
We report here that Tomatidine, the aglycon form of the plant secondary metabolite tomatine, has a potent growth inhibitory activity against SCVs (MIC of 0.12 μg/ml), whereas the growth of normal S. aureus strains was not significantly altered by Tomatidine (MIC, >16 μg/ml). The specific action of Tomatidine was bacteriostatic for SCVs and was clearly associated with their dysfunctional electron transport system, as the presence of the electron transport inhibitor 4-hydroxy-2-heptylquinoline-N-oxide (HQNO) caused normal S. aureus strains to become susceptible to Tomatidine. Inversely, the complementation of SCVs' respiratory deficiency conferred resistance to Tomatidine. Tomatidine provoked a general reduction of macromolecular biosynthesis but more specifically affected the incorporation of radiolabeled leucine in proteins of HQNO-treated S. aureus at a concentration corresponding to the MIC against SCVs. Furthermore, Tomatidine inhibited the intracellular replication of a clinical SCV in polarized CF-like epithelial cells.
CONCLUSIONS:
Our results suggest that Tomatidine eventually will find some use in combination therapy with other traditional antibiotics to eliminate persistent forms of S. aureus.

Tomatidine, a tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting acyl-CoA:cholesterol acyl-transferase (ACAT).[Pubmed: 22224814]

J Agric Food Chem. 2012 Mar 14;60(10):2472-9.

It was previously revealed that esculeoside A, a new glycoalkaloid, and esculeogenin A, a new aglycon of esculeoside A, contained in ripe tomato ameliorate atherosclerosis in apoE-deficent mice.
METHODS AND RESULTS:
This study examined whether Tomatidine, the aglycone of tomatine, which is a major tomato glycoalkaloid, also shows similar inhibitory effects on cholesterol ester (CE) accumulation in human monocyte-derived macrophages (HMDM) and atherogenesis in apoE-deficient mice. Tomatidine significantly inhibited the CE accumulation induced by acetylated LDL in HMDM in a dose-dependent manner. Tomatidine also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that Tomatidine suppresses both ACAT-1 and ACAT-2 activities. Furthermore, the oral administration of Tomatidine to apoE-deficient mice significantly reduced levels of serum cholesterol, LDL-cholesterol, and areas of atherosclerotic lesions.
CONCLUSIONS:
The study provides the first evidence that Tomatidine significantly suppresses the activity of ACAT and leads to reduction of atherogenesis.

Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy.[Pubmed: 24719321]

J Biol Chem. 2014 May 23;289(21):14913-24.

Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy.
METHODS AND RESULTS:
To address this problem, we used a systems-based discovery strategy to search for a small molecule whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, Tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that Tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, Tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity.
CONCLUSIONS:
Collectively, these results identify Tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy.