Platinum cyclooctadiene complexes with activity against gram-positive bacteria

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Number of pages8
JournalChemMedChem
Early online date8 Jul 2021
DOIs
Publication statusE-pub ahead of print - 8 Jul 2021

Bibliographical note

Funding Information:
This study was performed in strict accordance with The Australian Code for the Responsible Conduct of Research (2018). ATCC yeast and bacteria strains, and HEK‐293 cells were acquired from the American Type Culture Collection (ATCC). Human blood was sourced from the Australian Red Cross Blood Service with informed consent and its use in haemolysis assays was approved by The University of Queensland Institutional Human Research Ethics Committee, Approval Number 2014000031. The antimicrobial screening performed by CO‐ADD (The Community for Antimicrobial Drug Discovery) was funded by the Wellcome Trust (UK; Strategic Funding Award: 104797/Z/14/Z) and The University of Queensland (Australia; Strategic Funding Award). A.F. thanks the Swiss National Science Foundation for Support by an Early Postdoc. Mobility fellowship (P2ZHP2_177997). M.A.T.B., A.G.E., J.Z. S.R. and G.L. are supported in part by Wellcome Trust Strategic Grant WT1104797/Z/14/Z. A.K.C was supported by an Australian Research Council (ARC) DECRA fellowship (DE180100929). Furthermore, we acknowledge the DFG‐core facility Molecule Archive (DFG project number: 284178167) the management and provision of compounds for screening and in particular Alexander Braun, Angela Wandler, Mirja Dinkel (neé Enders) and Vikas Aggarwal for their contributions.

Publisher Copyright:
© 2021 Wiley-VCH GmbH

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • antibiotic
  • inorganic medicinal chemistry
  • metalloantibiotic
  • metals in medicine
  • platinum

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