Biguanide Iridium(III) Complexes with Potent Antimicrobial Activity

We have synthesized
novel organoiridium­(III) antimicrobial complexes
containing a chelated biguanide, including the antidiabetic drug metformin.
These 16- and 18-electron complexes were characterized by NMR, ESI-MS,
elemental analysis, and X-ray crystallography. Several of these complexes
exhibit potent activity against Gram-negative bacteria and Gram-positive
bacteria (including methicillin-resistant Staphylococcus aureus (MRSA)) and high antifungal potency toward C. albicans and C. neoformans, with minimum inhibitory concentrations
(MICs) in the nanomolar range. Importantly, the complexes exhibit
low cytotoxicity toward mammalian cells, indicating high selectivity.
They are highly stable in broth medium, with a low tendency to generate
resistance mutations. On coadministration, they can restore the activity
of vancomycin against vancomycin-resistant Enterococci (VRE). Also the complexes can disrupt and eradicate bacteria in
mature biofilms. Investigations of reactions with biomolecules suggest
that these organometallic complexes deliver active biguanides into
microorganisms, whereas the biguanides themselves are inactive when
administered alone.