title: Antimicrobial action of copper is amplified via inhibition of heme biosynthesis.
abstract: Copper (Cu) is a potent antimicrobial agent. Its use as a disinfectant goes back to antiquity, but this metal ion has recently emerged to have a physiological role in the host innate immune response. Recent studies have identified iron-sulfur containing proteins as key targets for inhibition by Cu. However, the way in these effects at the molecular level translate into a global effect on cell physiology is not fully understood. Here, we provide a new insight into the way in which Cu poisons bacteria. Using a copA mutant of the obligate human pathogen Neisseria gonorrhoeae that lacks a Cu efflux pump, we showed that Cu overloading led to an increased sensitivity to hydrogen peroxide. However, instead of promoting disproportionation of H2O2 via Fenton chemistry, Cu treatment led to an increased lifetime of H2O2 in cultures as a result of a marked decrease in catalase activity. We showed that this observation correlated with a loss of intracellular heme. We further established that Cu inhibited the pathway for heme biosynthesis. We proposed that this impaired ability to produce heme during Cu stress would lead to the failure to activate hemoproteins that participate in key processes, such as the detoxification of various reactive oxygen and nitrogen species, and aerobic respiration. The impact would be a global disruption of cellular biochemistry and an amplified Cu toxicity.
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland , St Lucia, Queensland 4072, Australia.
authors.forename: Karrera Y
authors.initials: KY
authors.lastname: Djoko
authors.forename: Alastair G
authors.initials: AG
authors.lastname: McEwan
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000494:pharmacology*; D003576:Electron Transport Complex IV / Q000378:metabolism; D006418:Heme / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006861:Hydrogen Peroxide / Q000378:metabolism; D009344:Neisseria gonorrhoeae / Q000187:drug effects* / Q000201:enzymology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D017382:Reactive Oxygen Species; D006418:Heme; D003300:Copper; D006861:Hydrogen Peroxide; C414443:cbb3 oxidase; D003576:Electron Transport Complex IV