Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics

Djoko, Karrera Y.; Goytia, Maira M.; Donnelly, Paul S.; Schembri, Mark A.; Shafer, William M.; McEwan, Alastair G.

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.

Citation

Djoko, K. Y., Goytia, M. M., Donnelly, P. S., Schembri, M. A., Shafer, W. M., & McEwan, A. G. (2015). Copper(II)-Bis(Thiosemicarbazonato) Complexes as Antibacterial Agents: Insights into Their Mode of Action and Potential as Therapeutics. Antimicrobial Agents and Chemotherapy, 59(10), 6444-6453. https://doi.org/10.1128/aac.01289-15

• Journal Article Type: Article
• Acceptance Date: Jul 23, 2015
• Online Publication Date: Aug 3, 2015
• Publication Date: Oct 1, 2015
• Deposit Date: Sep 6, 2017
• Publicly Available Date: Jul 18, 2018
• Journal: Antimicrobial Agents and Chemotherapy
• Print ISSN: 0066-4804
• Electronic ISSN: 1098-6596
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 59
• Issue: 10
• Pages: 6444-6453
• DOI: https://doi.org/10.1128/aac.01289-15
• Public URL: https://durham-repository.worktribe.com/output/1350304