Anti-staphylococcal activity of celastrol

The use of different species of plants of the Celastraceae family in folk medicine of various countries is well known. Among the secondary metabolites known from that family are nortriterpene quinone methides with the friedo-oleane skeleton, which show antitumor and antibiotic activities. They are isolated exclusively from the Celastraceae and Hippocrataceae and are considered chemotaxonomic indicators [1]. Celastrol, is a quinone methide that exhibit antimicrobial activity against Gram positive bacteria [2]. However, due to the lack information on the mechanism of action of this compound, we have performed a research about their antibacterial properties against Staphylococcus aureus. Comparison of MIC values of the celastrol with the other related-compounds allow us to conclude that conjugation in rings A and B and a functional group in ring E (C = O, COOH or OH) are structural requirements for anti-staphylococcal activity. The killing curves show that celastrol, added at lag and log phase of growth, at 20 µg/mL exhibits bacteriostatic effect (≤3 log10 in CFU/mL reduction) and that this action is not dependent on the starting inoculum. The macromolecular synthesis studies verified a cessation of all precursor incorporation but not simultaneously; however, these blocked was due to an inhibition of the molecules transport into the cells as consequence of injures produced on cytoplasmic membrane after treatment with celastrol. In fact, celastrol produced a marked and rapid efflux of intracellular potassium and an inhibition of NADH oxidation on membrane preparation from S. aureus, similarly as previously reported in human cells [3]. However, membrane damage was not revealed by the LIVE/DEAD Baclight assay or measurement of intracellular constituent efflux, absorbing at 260 and 280nm. Permeability changes in the cytoplasmic membrane and non-simultaneous cessation of macromolecular synthesis support the idea that celastrol could act on multiple targets on S. aureus.

Keywords: Celastrol, quinone methide, Staphylococcus aureus, antibacterial properties

References:

[1] González AG et al. Ethnobotanical uses of Celastraceae. Bioactive Metabolites. In: A. Rahman (Ed.), Studies in Natural Products Chemistry, Bioactive Natural Products (Part D). Elsevier: Amsterdam, 2000, pp. 649 – 738.

[2] Moujir L et al. The Relationship between Structure and Antimicrobial Activity in Quinones from the Celastraceae. Biochem Syst. Ecol. 1990; 18: 25 – 28.

[3] Jaquet V et al. NADPH oxidase (NOX) isoforms are inhibited by celastrol with a dual mode of action. Br J Pharmacol. 2011; 164:507 – 250.