Platinum Cyclooctadiene Complexes with Activity against Gram-positive Bacteria.

Angelo Frei,Amy K Cain,Soumya Ramu,Lucie Semenec,Johannes Zuegg,Nicole Jung,Stefan Bräse,Anke Deckers,Mark A T Blaskovich,Hue Dinh,Alysha G Elliott,Gabrielle J Lowe

doi:10.1002/cmdc.202100157

Abstract

Antimicrobial resistance is a looming health crisis, and it is becoming increasingly clear that organic chemistry alone is not sufficient to continue to provide the world with novel and effective antibiotics. Recently there has been an increased number of reports describing promising antimicrobial properties of metal‐containing compounds. Platinum complexes are well known in the field of inorganic medicinal chemistry for their tremendous success as anticancer agents. Here we report on the promising antibacterial properties of platinum cyclooctadiene (COD) complexes. Amongst the 15 compounds studied, the simplest compounds Pt(COD)X2 (X=Cl, I, Pt1 and Pt2) showed excellent activity against a panel of Gram‐positive bacteria including vancomycin and methicillin resistant Staphylococcus aureus. Additionally, the lead compounds show no toxicity against mammalian cells or haemolytic properties at the highest tested concentrations, indicating that the observed activity is specific against bacteria. Finally, these compounds showed no toxicity against Galleria mellonella at the highest measured concentrations. However, preliminary efficacy studies in the same animal model found no decrease in bacterial load upon treatment with Pt1 and Pt2. Serum exchange studies suggest that these compounds exhibit high serum binding which reduces their bioavailability in vivo, mandating alternative administration routes such as e. g. topical application.

Highlights

The rapid emergence and spread of multi-drug resistant bacteria coupled with a severe lack of new and effective antibiotics in the drug development pipeline create an enormous need for innovative approaches.[1]
In contrast to vancomycin, no loss of activity was observed against the multidrug resistant (MDR) strain or the clinical isolate with VanA resistance, whereas vancomycin did not show any antibacterial activity at the tested concentrations
We have described a new class of antibacterial platinum complexes based on the COD-ligand scaffold

Summary

Introduction

The rapid emergence and spread of multi-drug resistant bacteria coupled with a severe lack of new and effective antibiotics in the drug development pipeline create an enormous need for innovative approaches.[1]. This article belongs to the joint Special Collection with the European Journal of Inorganic Chemistry, “Metals in Medicine” It was already observed by Rosenberg et al in 1966, that platinum(IV) complexes inhibited the growth of Escherichia coli.[7] probably since infections were largely effectively controlled by existing antibiotics, attention shifted to the more urgent search for new anticancer treatments. Metal complexes have only recently gathered attention in the antimicrobial field with multiple reports describing several classes of compounds with promising in vitro and in vivo results.[10]. Platinum was the element with the largest absolute number of non-toxic actives in the whole dataset Based on these results we decided to further investigate the most abundant class of compounds in this set, the organometallic 1,5-cyclooctadiene (COD) platinum complexes. We report on the antibacterial properties of 14 platinum(COD) complexes, their broad Gram-positive activity spectrum and preliminary in vivo toxicity and efficacy data in the wax moth larvae model Galleria mellonella

Results and Discussion

Conclusion

Conflict of Interest