title: Copper complexation screen reveals compounds with potent antibiotic properties against methicillin-resistant Staphylococcus aureus.
abstract: Macrophages take advantage of the antibacterial properties of copper ions in the killing of bacterial intruders. However, despite the importance of copper for innate immune functions, coordinated efforts to exploit copper ions for therapeutic interventions against bacterial infections are not yet in place. Here we report a novel high-throughput screening platform specifically developed for the discovery and characterization of compounds with copper-dependent antibacterial properties toward methicillin-resistant Staphylococcus aureus (MRSA). We detail how one of the identified compounds, glyoxal-bis(N4-methylthiosemicarbazone) (GTSM), exerts its potent strictly copper-dependent antibacterial properties on MRSA. Our data indicate that the activity of the GTSM-copper complex goes beyond the general antibacterial effects of accumulated copper ions and suggest that, in contrast to prevailing opinion, copper complexes can indeed exhibit species- and target-specific activities. Based on experimental evidence, we propose that copper ions impose structural changes upon binding to the otherwise inactive GTSM ligand and transfer antibacterial properties to the chelate. In turn, GTSM determines target specificity and utilizes a redox-sensitive release mechanism through which copper ions are deployed at or in close proximity to a putative target. According to our proof-of-concept screen, copper activation is not a rare event and even extends to already established drugs. Thus, copper-activated compounds could define a novel class of anti-MRSA agents that amplify copper-dependent innate immune functions of the host. To this end, we provide a blueprint for a high-throughput drug screening campaign which considers the antibacterial properties of copper ions at the host-pathogen interface.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
authors.forename: Mehri
authors.initials: M
authors.lastname: Haeili
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Moore
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Christopher J C
authors.initials: CJ
authors.lastname: Davis
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Cochran
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Chemistry, College of Arts & Sciences, Kansas State University, Manhattan, Kansas, USA Department of Anatomy Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, USA.
authors.forename: Tej B
authors.initials: TB
authors.lastname: Shrestha
authors.affiliation: Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Yaofang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, College of Arts & Sciences, Kansas State University, Manhattan, Kansas, USA.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Bossmann
authors.affiliation: Department of Pathology, Division of Laboratory Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Benjamin
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA okutsch@uab.edu fwolsche@uab.edu.
authors.forename: Olaf
authors.initials: O
authors.lastname: Kutsch
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA okutsch@uab.edu fwolsche@uab.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Wolschendorf
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D007113:Immunity, Innate / Q000187:drug effects; D008024:Ligands; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D056831:Coordination Complexes; D008024:Ligands; D013882:Thiosemicarbazones; C000595457:glyoxal-bis(4-methylthiosemicarbazonato)copper(II); D003300:Copper
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