Antimicrobial Activity and Mode of Action of Celastrol, a Nortriterpen Quinone Isolated from Natural Sources

Abstract

Species of the Celastraceae family are traditionally consumed in different world regions for their stimulating properties. Celastrol, a triterpene methylene quinone isolated from plants of celastraceas, specifically activates satiety centers in the brain that play an important role in controlling body weight. In this work, the antimicrobial activity and mechanism of action of celastrol and a natural derivative, pristimerin, were investigated in Bacillus subtilis. Celastrol showed a higher antimicrobial activity compared with pristimerin, being active against Gram-positive bacteria with minimum inhibitory concentrations (MICs) that ranged between 0.16 and 2.5 µg/mL. Killing curves displayed a bactericidal effect that was dependent on the inoculum size. Monitoring of macromolecular synthesis in bacterial populations treated with these compounds revealed inhibition in the incorporation of all radiolabeled precursors, but not simultaneously. Celastrol at 3 µg/mL and pristimerin at 10 µg/mL affected DNA and RNA synthesis first, followed by protein synthesis, although the inhibitory action on the uptake of radiolabeled precursors was more dramatic with celastrol. This compound also caused cytoplasmic membrane disruption observed by potassium leakage and formation of mesosome-like structures. The inhibition of oxygen consumption of whole and disrupted cells after treatments with both quinones indicates damage in the cellular structure, suggesting the cytoplasmic membrane as a potential target. These findings indicate that celastrol could be considered as an interesting alternative to control outbreaks caused by spore-forming bacteria.

In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates

“…The antibacterial activity of celastrol was tested against CRK isolates with no inhibitory activity observed for concentrations up to 1024 µg ml −1 . This is consistent with previous study reported that celastrol showed low MIC against Gram-positive bacteria and no growth inhibitory activity against Gram-negative bacteria in the used concentration [ 12 ]. Our study presumed that celastrol possibly acts by the same mechanism on both Gram-positive and Gram-negative bacteria.…”

“…Celastrol has been recently exploited to treat obesity and type 2 diabetes mellitus [ 11 ]. In addition, celastrol has been found to exhibit a growth inhibitory activity against Gram-positive bacteria [ 12 ]. Furthermore, celastrol was found to reduce staphyloxanthin biosynthesis and biofilm formation in Staphylococcus aureus [ 13 , 14 ].…”

Proton Motive Force Inhibitors Are Detrimental to Methicillin-Resistant Staphylococcus aureus Strains

“…In addition, celastrol treatment makes B. subtilis cells elongated and spindle-shaped. Using transmission electron microscopy, celastrol has been shown to damage cell membranes to a certain extent ( 74 ).…”

PROTON MOTIVE FORCE INHIBITORS ARE DETRIMENTAL TO METHICILLIN-RESISTANTSTAPHYLOCOCCUS AUREUSPERSISTER CELLS

“…In addition, celastrol treatment makes B. subtilis cells elongated and spindle-shaped. Using transmission electron microscopy, celastrol has been shown to damage cell membranes to a certain extent 80 . Altogether, although the bactericidal effects of the identified PMF inhibitors (e.g., nordihydroguaiaretic acid, gossypol, trifluoperazine, amitriptyline, and alexidine) have already been highlighted in the literature, their effects on persister cells, to the best of our knowledge, have not been well characterized.…”