Methicillin-resistant Staphylococcus aureus (MRSA) is a notorious superbug that is potentially lifethreatening. 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 μg/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.

As eries of boron-containing lipids werep repared by reactions of cyclic oxonium derivatives of polyhedron boranesa nd metallacarboranes (closo-dodecaborate anion, cobalt and iron bis(dicarbollides)) with amine and carboxylic acids which are derived from cholesterol. Stable liposomal formulations,o nt he basis of synthesized boron-containing lipids, hydrogenated soybean l-a-phosphatidylcholinea nd (HSPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) as excipients,w ere prepared and then characterizedb yd ynamic light scattering(DLS) that revealed the formation of particles to be smaller than 200 nm in diameter.T he resulting liposomal formulationss howed moderate to excellent loading and entrapmente fficiency, thus justifying the design of the compounds to fit in the lipid bilayer and ensuringease of in vivo use for futurea pplication. The liposomalf ormulations based on cobalt and iron bis(dicarbollide)-based lipids were found to be nontoxic against both human breast normale pithelial cells MCF-10A and human breast cancer cells MCF-7.

Transmembrane translocation (flip-flop) of cobalt bis(dicarbollide) (COSAN) anions, elicited by application of a voltage-jump across the lipid bilayer membrane, manifested itself in monoexponential electrical current transients in the microsecond time scale. Halogenation of COSAN led to multi-fold acceleration of the flip-flop, the effect increasing with the molecular weight of the halogens. The exception was a fluorinated analog which exhibited slowing of the translocation kinetics. Measurements of the fluorescence ratio of the dye di-4-ANEPPS in lipid vesicles showed significant differences in the adsorption of studied hydrophobic anions. Based on these data, it can be concluded that COSAN and COSAN-F were located on the surface of the lipid membrane in the cisoid conformation increasing the dipole potential of the lipid membrane, while other halogenated COSAN analogs were adsorbed in the transoid conformation. Differences in the flip-flop kinetics of COSAN analogs were attributed to variation in the molecular volume of the anions and their orientation on the membrane surface.

Reactions of the iodonium derivative of cobalt bis(dicarbollide) anion [μ-8,8′-I-3,3′-Co(1,2-C2B9H10)2] with Lewis bases in aromatic solvents were studied. The reactions proceed through the iodonium bridge opening, and the structure of the reaction products depends strongly on the nature of the Lewis base and solvent used. The reactions with conventional Lewis bases (L) give the corresponding products of Lewis base addition, [8-L-8′-I-3,3′-Co(1,2-C2B9H10)2], whereas the reactions with sterically hindered Lewis bases (L*) result in activation of the C−H bond of the aromatic solvent with formation of the corresponding aryl derivatives [8-Ar-8′-I-3,3′-Co(1,2-C2B9H10)2]−. Activated arenes, such as toluene, could react with [μ-8,8′-I-3,3′-Co(1,2-C2B9H10)2] without Lewis bases, whereas strongly deactivated arenes do not give C−H activation products even in the presence of sterically hindered Lewis bases.