The continuous rise of antimicrobial resistance is a serious threat to human health and already causing hundreds of thousands of deaths each year. While natural products and synthetic organic small molecules have provided the majority of our current antibiotic arsenal, they are falling short in providing new drugs with novel modes of action able to treat multidrug resistant bacteria. Metal complexes have recently shown promising results as antimicrobial agents, but the number of studied compounds is still vanishingly small, making it difficult to identify promising compound classes or elucidate structure-activity relationships. To accelerate the pace of discovery we have applied a combinatorial chemistry approach to the synthesis of metalloantibiotics. Utilizing robust Schiff-base chemistry and combining 7 picolinaldehydes with 10 aniline derivatives, and 6 axial ligands, either imidazole/pyridine-based or solvent, we have prepared a library of 420 novel manganese tricarbonyl complexes. All compounds were evaluated for their antibacterial properties and 10 lead compounds were identified, re-synthesised and fully characterised. All 10 compounds showed high and broad activity against Gram-positive bacteria. The best manganese complex displayed low toxicity against human cells with a therapeutic index of >100. In initial mode of action studies, we show that it targets the bacterial membrane without inducing pore formation or depolarisation. Instead, it releases its carbon monoxide ligands around the membrane and inhibits the bacterial respiratory chain. This work demonstrates that large numbers of metal complexes can be accessed through combinatorial synthesis and evaluated for their antibacterial potential, allowing for the rapid identification of promising metalloantibiotic lead compounds.
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