A platinum butterfly effect: small changes turn an anticancer drug into a non-toxic metalloantibiotic with in vivo efficacy
Artikel i vetenskaplig tidskrift, 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.
Författare
Cagri Ozsan
Universität Bern
University of York
Ann-Britt Schäfer
Molekylär biovetenskap
Abdul Akhir
Central Drug Research Institute
Obed Akwasi Aning
Chalmers, Life sciences, Kemisk biologi
Sofia Fulgencio
Universität Bern
Rahul Maitra
Central Drug Research Institute
Rupa Rani
Chalmers, Life sciences, Kemisk biologi
Deepanshi Saxena
Central Drug Research Institute
Fredrik Westerlund
Molekylär biovetenskap
Sidharth Chopra
Central Drug Research Institute
Academy of Scientific and Innovative Research AcSIR
Michaela Wenzel
Molekylär biovetenskap
Angelo Frei
University of York
Universität Bern
NPJ ANTIMICROBIALS AND RESISTANCE
2731-8745 (eISSN)
Vol. 4 1 37Ämneskategorier (SSIF 2025)
Molekylärbiologi
Mikrobiologi
DOI
10.1038/s44259-026-00211-w
PubMed
42103893