A Platinum Butterfly Effect: Small Changes Turn an Anticancer Drug into a Non-toxic Metalloantibiotic with In Vivo Efficacy

Widespread resistance to all clinically used antibiotics has sparked investigations into alternative sources for novel and effective antimicrobial agents. Metal-based compounds (metalloantibiotics) have emerged as a promising class of potential antibiotics exhibiting high hit rates against critical bacterial pathogens while not displaying higher toxicity than organic compounds. Here, we describe the exploration of a novel class of non-toxic, Gram-positive acting platinum-based antibacterial agents with micro to nanomolar activity against a range of methicillin and vancomycin-resistantStaphylococcus aureusstrains. Structure-activity relationship (SAR) studies revealed that modifications of the core scaffold result in reduced antibacterial activity. Mode of action studies investigations showed that lead compoundPt1did not impair cell division, RNA, protein, or cell wall synthesis, nor did it affect membrane integrity or potential. Instead, akin to the structurally similar anticancer drug cisplatin (CisPt),Pt1treatment resulted in reduced DNA staining, visible nucleoid compaction, and activation of DNA damage repair responses. Importantly, we could show thatPt1is able to interact with and damage DNA directly, resulting in DNA strand breaks and fragmentation.Pt1activity can be reduced significantly by high amounts of a hydroxyl radical scavenger. DerivativePt8, which retained DNA-damaging activity but was less potent in terms of antibacterial activity, was not affected by the presence of radical scavengers, suggesting thatPt1possesses a multimodal mechanism. In line with this observation, no resistance development toPt1was observed over the course of 36 passages. Finally, we could demonstrate thein vivoactivity ofPt1, which significantly reduced the bacterial load in a murineS. aureusskin infection model. Altogether, these findings shed light on the SAR and antibacterial mode of action of a novel class of platinum metalloantibiotics, validate itsin vivoefficacy, and pave the way for further exploration of platinum compounds as novel drug candidates with a highly attractive activity profile.