Structural patterns enhancing the antibacterial activity of metallacarborane-based antibiotics

Abstract

Newly developed antibiotics are supposed to treat infections caused by drug-resistant bacteria. To increase the likelihood of overcoming resistance, antibiotic candidates should be based on structures that are unknown to bacteria. This is why boron-based antibiotics offer an interesting alternative to carbon-based drugs. This work is devoted to the development of a new group of antibiotics based on abiotic metallacarborane, cobalta bis(dicabrollide) (COSAN). We managed to identify the two most promising structural patterns that cause COSAN-based compounds to be selectively active toward S. aureus: the introduction of α-amino acid amide in the organic part of the molecule and the addition of iodine directly to the metallacarborane cage. The first modification provided selective activity of the tested compounds toward S. aureus over mammalian cells through proper hydrophobic-hydrophilic balance. The second modification increased all observed biological activities. The patterns proposed in this paper can be used in the development of metallacarborane-based antibiotics that have potent antibacterial properties and low cytotoxicity.