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

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

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 of the electron transport chain. We now show that these complexes are also toxic against a range of bacterial pathogens some of which 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 to the cytoplasm. Although the chemistry of Cu(btsc) complexes may dictate their mechanism of action, their efficacy depends highly on bacterial physiology which is linked to the ability of the 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 as a potential treatment against this significant bacterial pathogen.