Rationally designed ruthenium(II) complexes combat drug resistance in Staphylococcus aureus via type IIA topoisomerase inhibition
Abstract
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 ( RuBTI s). 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 RuBTI s are S. aureus type IIA topoisomerases. While RuBTI s 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.
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