Rationally designed ruthenium(II) complexes combat drug resistance in Staphylococcus aureus via type IIA topoisomerase inhibition

Drug-resistant infections continue to rise in frequency, constituting a global health crisis. With an estimated 1.14 million deaths attributed to antimicrobial resistance (AMR) in 2021, novel antibiotics are desperately needed. We herein report a new class of rationally designed antibiotic: ruthenium-based bacterial type IIA topoisomerase inhibitors (RuBTIs). Our compounds C4 and C5, are potent inhibitors of Staphylococcus aureus, and showed excellent inhibition of clinical isolates and drug-resistant strains, including methicillin-resistant S. aureus, a WHO high-priority pathogen. Importantly, C4 and C5 showed no inhibition of mammalian cell lines. Enzymatic assays, transcriptomics, and crystallography show that the primary targets of our RuBTIs are S. aureus type IIA topoisomerases. While RuBTIs share these targets with quinolones and novel type IIA topoisomerase inhibitors (NBTIs), C4 and C5 maintain potency in NBTI and quinolone resistant strains. This indicates that this is a new class of drug with excellent potential to address AMR by evading existing resistance mechanisms.