Robotic Click Chemistry for Metal-Organic Antibiotic Discovery

The rapid global emergence of antimicrobial resistance (AMR) has significantly reduced the effectiveness of existing antibiotics, creating an urgent need for innovative discovery strategies and structurally novel antimicrobial agents. Metal-organic complexes represent a promising but underexplored chemical space due to their unique redox properties, three-dimensional architectures, and ability to engage biological targets through mechanisms distinct from traditional organic antibiotics. However, systematic exploration of this chemical space has historically been limited by labour-intensive synthetic procedures and low-throughput workflows. In this study, we report the development of an integrated robotic synthesis and screening platform that combines high-throughput automation with copper-catalysed azide–alkyne cycloaddition (CuAAC) click chemistry for the rapid generation of metal-organic antibiotic candidates. Using a modular combinatorial design strategy, 216 triazole-based ligands were synthesized and subsequently coordinated with five transition metal centers (Pd, Ru, Ir, Cu, and Ag), resulting in a focused library of 720 structurally diverse metal-organic complexes. Automated liquid handling, reaction monitoring via UPLC-MS, and standardized purification protocols enabled efficient synthesis with high reproducibility and an average isolated yield exceeding 70%. Biological evaluation of the compound library was performed using minimum inhibitory concentration (MIC) assays against representative Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacterial strains. Several iridium-based complexes demonstrated potent antibacterial activity, with MIC values as low as 1–2 µg/mL against S. aureus, while maintaining low cytotoxicity toward human HEK-293 cells. Structure–activity relationship analysis revealed that heteroaromatic substitution on the triazole scaffold enhanced antimicrobial potency, suggesting improved bacterial target engagement or membrane interaction. The integration of robotics with click chemistry substantially reduced synthesis time, minimized human error, and enabled rapid iteration between design and biological testing. This study demonstrates that automated combinatorial metal-organic chemistry is a viable and scalable approach for antibiotic discovery. Beyond identifying promising lead compounds, the platform establishes a generalizable framework for accelerating exploration of nontraditional chemical modalities in the fight against antimicrobial resistance.