Celastrol: a natural compound with antibacterial properties. Mode of action against Staphylococcus epidermidis

The methylene quinone celastrol is a natural compound present in plant species of the Celastraceae family that has shown antibacterial properties against Staphylococcus epidermidis [1]. This Coagulase-negative Staphylococci (CoNS) is commonly found as a skin commensal and is considered the primary cause of CoNS-related infections, particularly in nosocomial settings [2]. This work presents a first approach to elucidate the mechanism of action of celastrol on S. epidermidis. Exposure of S. epidermidis cultures to celastrol revealed a bactericidal effect that was positively associated with drug concentration, inversely related to the size of the bacterial inoculum, and conditioned by the chemical composition of the growing media. The electron micrographs, Back-light test, and the measurement of oxygen consumption did not show notable damage to external structures such as the cell wall or the plasma membrane, although treated cultures showed alterations in the formation of septa during cell division. The evaluation of the macromolecular synthesis, and the uptake of its precursors showed that celastrol at 15 μg/ml had the most severe effect on peptidoglycan synthesis by inhibiting the incorporation and uptake of N-Acetylglucosamine by>50% in 2 and 10 minutes, respectively. Glucose uptake was also immediately inhibited by celastrol by>60% within 2 minutes. These data suggest that celastrol could primarily target cell wall synthesis and compromise cell division. This study raises a first hypothesis about the effect of celastrol against S. epidermidis, although additional evaluations are necessary to obtain a more precise understanding of its mechanism of action.