title: Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics.
abstract: There is increasing interest in the use of lipophilic copper (Cu)-containing complexes to combat bacterial infections. In this work, we showed that Cu complexes with bis(thiosemicarbazone) ligands [Cu(btsc)] exert antibacterial activity against a range of medically significant pathogens. Previous work using Neisseria gonorrhoeae showed that Cu(btsc) complexes may act as inhibitors of respiratory dehydrogenases in the electron transport chain. We now show that these complexes are also toxic against pathogens that lack a respiratory chain. Respiration in Escherichia coli was slightly affected by Cu(btsc) complexes, but our results indicate that, in this model bacterium, the complexes act primarily as agents that deliver toxic Cu ions efficiently into the cytoplasm. Although the chemistry of Cu(btsc) complexes may dictate their mechanism of action, their efficacy depends heavily on bacterial physiology. This is linked to the ability of the target bacterium to tolerate Cu and, additionally, the susceptibility of the respiratory chain to direct inhibition by Cu(btsc) complexes. The physiology of N. gonorrhoeae, including multidrug-resistant strains, makes it highly susceptible to damage by Cu ions and Cu(btsc) complexes, highlighting the potential of Cu(btsc) complexes (and Cu-based therapeutics) as a promising treatment against this important bacterial pathogen.
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia k.djoko@uq.edu.au mcewan@uq.edu.au.
authors.forename: Karrera Y
authors.initials: KY
authors.lastname: Djoko
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Maira M
authors.initials: MM
authors.lastname: Goytia
authors.affiliation: School of Chemistry and Bio21 Institute of Molecular Science and Biotechnology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Mark A
authors.identifier: http://orcid.org/0000-0003-4863-9260
authors.initials: MA
authors.lastname: Schembri
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, Georgia, USA Laboratories of Bacterial Pathogenesis, Veterans Affairs Medical Center, Decatur, Georgia, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Shafer
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia k.djoko@uq.edu.au mcewan@uq.edu.au.
authors.forename: Alastair G
authors.initials: AG
authors.lastname: McEwan
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000633:toxicity*; D001692:Biological Transport; D056831:Coordination Complexes / Q000737:chemistry / Q000633:toxicity*; D003300:Copper / Q000737:chemistry / Q000633:toxicity*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004579:Electron Transport / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006193:Haemophilus influenzae / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D007779:Lactobacillus acidophilus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009344:Neisseria gonorrhoeae / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013045:Species Specificity; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013882:Thiosemicarbazones / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000900:Anti-Bacterial Agents; D056831:Coordination Complexes; D013882:Thiosemicarbazones; D003300:Copper