Cyanide enhances hydrogen peroxide toxicity by recruiting endogenous iron to trigger catastrophic chromosomal fragmentation

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Abstract

Summary

Hydrogen peroxide (HP) or cyanide (CN) are bacteriostatic at low-millimolar concentrations for growingEscherichia coli, whereas CN + HP mixture is strongly bactericidal. We show that this synergistic toxicity is associated with catastrophic chromosomal fragmentation. Since CN alone does not kill at any concentration, while HP alone kills at 20 mM, CN must potentiate HP poisoning. The CN + HP killing is blocked by iron chelators, suggesting Fenton's reaction. Indeed, we show that CN enhances plasmid DNA relaxation due to Fenton's reactionin vitro. However, mutants with elevated iron or HP pools are not acutely sensitive to HP-alone treatment, suggesting that, in addition,in vivoCN recruits iron from intracellular depots. We found that part of the CN-recruited iron pool is managed by ferritin and Dps: ferritin releases iron on cue from CN, while Dps sequesters it, quelling Fenton's reaction. We propose that disrupting intracellular iron trafficking is a common strategy employed by the immune system to kill microbes.

Hydrogen peroxide and cyanide synergistically kill E. coli via Fenton's reaction (Fe(II)+H2O2–>OH·) unleashing catastrophic chromosomal fragmentation. We show in vitro that cyanide enhances Fenton on DNA. Our genetic investigation reveal that the second mechanism of cyanide potentiation of this Fenton's reaction is via iron recruitment from ferritin iron distribution centers. At the same time, the iron depot Dps acts to protect the chromosome from this massive oxidative damage.

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