A Highly Potent Antibacterial Agent Targeting Methicillin-Resistant Staphylococcus aureus Based on Cobalt Bis(1,2-Dicarbollide) Alkoxy Derivative

Methicillin-resistant Staphylococcus aureus (MRSA) is a notorious superbug that is potentially life- threatening. Among conventional antibiotics, vancomycin is a "gold standard" agent used to treat serious MRSA infections. Such therapy, however, is often ineffective because of the emergence of less-susceptible strains. Therefore, the exploration of new antimicrobial agents, especially nonantibiotic drugs, to cope with the growing threat of MRSA has become an urgent necessity. Herein, we have investigated the possibility to develop a metallacarborane antimicrobial agent, cobalt bis(1,2-dicarbollide) alkoxy derivative (K121), and we have evaluated the relevant anti-MRSA behaviors. We demonstrated that K121 has a dose-dependent anti-MRSA activity with a low minimal inhibitory concentration of 8 mu g/mL and a high selectivity over mammalian cells. In particular, a high bacteria-killing efficiency was observed with eradication of all MRSA cells within 30 min. In addition, K121 showed a high inhibition effect on the formation of bacterial biofilm. More importantly, unlike vancomycin, a repeated use of K121 would not induce drug resistance even after 20 passages of MRSA. The mechanistic study showed that K121 kills MRSA by inducing an increase in the reactive oxygen species (ROS) production and consequentially inducing irreversible damage to the cell wall/membrane, which ultimately leads to the death of MRSA. Our results suggested that K121 may be used as a promising nonantibiotic therapeutic agent against MRSA infections in future clinical practices.