Water soluble organometallic small molecules as promising antibacterial agents: synthesis, physical-chemical properties and biological evaluation to tackle bacterial infections

Abstract

The Na[3,3'-Fe(8-I-1,2-C₂B₉H₁₀)₂] and Na[2,2'-M(1,7-C₂B₉H₁₁)] (M = Co³⁺, Fe³⁺) small molecules are synthesized and the X-ray structures of [(H₃O)(H₂O)₅][2,2'-Co(1,7-C₂B₉H₁₁)₂] and [Cs(MeCN)][8,8'-I₂-Fe(1,2 C₂B₉H₁₀)₂], both displaying a transoid conformation of the [M(C₂B₉)₂]^- framework, are reported. Importantly, the supramolecular structure of [(H₃O)(H₂O)₅][2,2'-Co(1,7-C₂B₉H₁₁)₂] presents 2D layers leading to a lamellar arrangement of the anions while the cation layers form polymeric water rings made of six- and four-membered rings of water molecules connected via OH⋯H hydrogen bonds; B-H⋯O contacts connect the cationic and anionic layers. Herein, we highlight the influence of the ligand isomers (ortho-/meta-), the metal effect (Co³⁺/Fe³⁺) on the same isomer, as well as the influence of the presence of the iodine atoms on the physical-chemical and biological properties of these molecules as antimicrobial agents to tackle antibiotic-resistant bacteria, which were tested with four Gram-positive bacteria, five Gram-negative bacteria, and three Candida albicans strains that have been responsible for human infections. We have demonstrated an antimicrobial effect against Candida species (MIC of 2 and 3 nM for Na[3,3'-Co(8-I-1,2-C₂B₉H₁₀)₂] and Na[2,2'-Co(1,7-C₂B₉H₁₁)₂], respectively), and against Gram-positive and Gram-negative bacteria, including multiresistant MRSA strains (MIC of 6 nM for Na[3,3'-Co(8-I-1,2-C₂B₉H₁₀)₂]). The selectivity index for antimicrobial activity of Na[3,3'-Co(1,2-C₂B₉H₁₁)₂] and Na[3,3'-Co(8-I-1,2-C₂B₉H₁₀)₂] compounds is very high (165 and 1180, respectively), which reveals that these small anionic metallacarborane molecules may be useful to tackle antibiotic-resistant bacteria. Moreover, we have demonstrated that the outer membrane of Gram-negative bacteria constitutes an impermeable barrier for the majority of these compounds. Nonetheless, the addition of two iodine groups in the structure of the parent Na[3,3'-Co(1,2-C₂B₉H₁₁)₂] had an improved effect (3-7 times) against Gram-negative bacteria. Possibly the changes in their physical-chemical properties make the meta-isomers and the ortho-di-iodinated small molecules more permeable for crossing this barrier. It should be emphasized that the most active metallabis(dicarbollide) small molecules are both transoid conformers in contrast to the ortho- [3,3'-Co(1,2-C₂B₉H₁₁)₂]^- that is cisoid. The fact that these small molecules cross the mammalian membrane and have antimicrobial properties but low toxicity for mammalian cells (high selectivity index, SI) represents a promising tool to treat infectious intracellular bacteria. Since there is an urgent need for antibiotic discovery and development, this study represents a relevant advance in the field.