A platinum butterfly effect: small changes turn an anticancer drug into a non-toxic metalloantibiotic with in vivo efficacy
Journal article, 2026
Metal-based compounds have emerged as a promising class of potential antibiotics exhibiting highhit-rates against critical bacterial pathogens while not displaying higher toxicity than organic compounds. Here, we describe the exploration of novel, non-toxic, Gram-positive acting platinum-basedantibacterialagentswithhighactivity.Structure-activityrelationship(SAR)studies revealed that the simplest scaffold showed the best antibacterial properties. Mode of action studies showed that lead compoundPt1akin to the structurally similar chemotherapeutic cisplatin, causes reduced DNA staining, visible nucleoid compaction, and activation of DNA damage repair responses. Importantly, we show thatPt1interacts with and damages DNA directly, resulting in DNA strand breaks andfragmentation.Pt1activity can be reduced by hydroxyl radical scavengers, suggesting thatPt1possesses a multimodal mechanism. In line with this observation, no resistance development toPt1was observed. Finally, we demonstrate the in vivo activity ofPt1, which significantly reduced the bacterial load in a murine S. aureus skin infection model. These findings shed light on the SAR and antibacterial mode of action of a novel class of platinum metallo antibiotics, validate their in vivo efficacy, and pave the way for further exploration of platinum compounds as novel antibiotic drug candidates.
Author
Cagri Ozsan
University of Bern
University of York
Ann-Britt Schäfer
Molecular Bioscience
Abdul Akhir
Central Drug Research Institute
Obed Akwasi Aning
Chalmers, Life Sciences, Chemical Biology
Sofia Fulgencio
University of Bern
Rahul Maitra
Central Drug Research Institute
Rupa Rani
Chalmers, Life Sciences, Chemical Biology
Deepanshi Saxena
Central Drug Research Institute
Fredrik Westerlund
Molecular Bioscience
Sidharth Chopra
Central Drug Research Institute
Academy of Scientific and Innovative Research AcSIR
Michaela Wenzel
Molecular Bioscience
Angelo Frei
University of York
University of Bern
NPJ ANTIMICROBIALS AND RESISTANCE
2731-8745 (eISSN)
Vol. 4 1 37Subject Categories (SSIF 2025)
Molecular Biology
Microbiology
DOI
10.1038/s44259-026-00211-w
PubMed
42103893