Structural patterns enhancing the antibacterial activity of metallacarborane-based antibiotics

Each year, the number of infections caused by multidrug-resistant bacteria is increasing, making new public health crises likely in the future. To prevent this, novel drugs capable of overcoming current resistances are needed. Boron cluster-based antibiotics offer a valuable possibility to create a new class of antibiotics and expand antibiotic's chemical space beyond conventional carbon-based molecules. In this work, we identified the two most promising structural patterns providing cobalta bis(dicabrollide)(COSAN)-based compounds with potent and selective activity toward Staphylococcus aureus (including clinical strains): introduction of the -amino acid amide to the molecule and the addition of iodine directly to the metallacarborane cage. Furthermore, we found that proper hydrophobic-hydrophilic balance is crucial for the selective activity of the tested compounds toward S. aureus over mammalian cells. The patterns proposed in this paper can be useful in the development of metallacarborane-based antibiotics with potent antibacterial properties and low cytotoxicity.