Discovery of Phototoxic Metal Complexes with Antibacterial Properties via a Combinatorial Approach

Antimicrobial resistance is one of the biggest global healthcare challenges. Therefore, there is an urgent need to develop new molecules that display distinct antibacterial properties to overcome resistance. With this aim, we have developed a combinatorial and semiautomated platform to synthesize and screen a library of 78 compounds against Gram-positive and Gram-negative bacteria. This library is based on octahedral iridium(III) complexes with general formula [Ir(CN)₂(NN)]Cl (where CN are cyclometallating polyaromatic ligands and NN are phenanthroline-imidazole or dipyridophenazine derivatives) which are known to generate reactive oxygen species (ROS) upon light irradiation. From the initial screen of the entire library (in the dark and under light irradiation) against Escherichia coli and Staphylococcus aureus, we show that this scaffold is highly effective at inhibiting growth of Gram-positive bacteria at an intermediate dose (16 μg/mL), displaying a hit rate of >30% in the dark and rising to 56% under light irradiation. Six complexes were selected for further studies against a panel of five Gram-positive strains, allowing us to identify two lead complexes with MICs as low as 2 μg/mL. These complexes were studied in more detail to establish their mode of action using a time-kill study against the S. aureus USA300 strain.

A combinatorial and semiautomated approach has been used to synthesize and screen a library of 78 photoactive iridium(III) complexes against Gram-positive and Gram-negative bacteria. Through three subsequent rounds of testing, two lead compounds were identified which display high activity upon light irradiation against S. aureus US300.