New classes of antibiotics are desperately needed to treat drug-resistant infections. Metal complexes are ubiquitous in synthetic organic chemistry as catalysts, but only play a limited role in medicinal chemistry research. However, anticancer therapies based on metal complexes such as cisplatin are clinically important, and other metal-based compounds are in clinical trials.1
The Community for Open Antimicrobial Drug Discovery (CO-ADD) is a global open access initiative that has screened over 330,000 diverse compounds for their antimicrobial activity, sourced from over 330 academic groups.1 Within this unique collection are over 1000 metal complexes that have been submitted by collaborators, containing 32 different metals.
An analysis of the CO-ADD database shows that the hit-rate for metal complexes is more than ten-fold higher than that of purely organic compounds, even after accounting for cytotoxicity. Within the set, we can identify trends for which types of metals/structures seem to be consistently more active. While our initial analysis focused on antibacterial activity,3 further studies have now shown similar benefits for antifungal activity.4 A subset of these complexes have been advanced into more comprehensive testing to assess their potential as antibiotics, including in vivo studies in a Galleria mellonella moth larvae model.
Our results show that metal complexes are a promising new chemical class for the sourcing new antibiotics. The diverse 3D geometry of these ‘metallobiotics’ enables a higher degree of structural variety than their organic counterparts, implying an enormous landscape of unexplored chemical space. Metal complexes can also access unique modes of action that differ from organic compounds. We hope to increase the number of metal compounds in CO-ADD’s database to allow for a better understanding of trends in activities, and to enable the development of new classes of metal-based antibiotics for clinical evaluation.