School of Chemistry and Molecular Biosciences, The University of Queensland , St Lucia, Queensland 4072, Australia.
ACS Chem Biol. 2013 Oct 18;8(10):2217-23. doi: 10.1021/cb4002443. Epub 2013 Aug 22.
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.
铜（Cu）是一种有效的抗菌剂。它作为消毒剂的使用可以追溯到古代，但最近发现这种金属离子在宿主先天免疫反应中具有生理作用。最近的研究已经确定含铁硫的蛋白质是 Cu 抑制的关键靶标。然而，这些在分子水平上的影响如何转化为对细胞生理学的全面影响还不完全清楚。在这里，我们提供了一个关于 Cu 毒害细菌的新视角。使用一种缺乏铜外排泵的专性人类病原体淋病奈瑟菌的 copA 突变体，我们表明 Cu 过载会导致对过氧化氢的敏感性增加。然而，Cu 处理并没有通过芬顿化学促进 H2O2 的歧化，而是由于过氧化氢酶活性的显著降低，导致培养物中 H2O2 的寿命延长。我们表明，这一观察结果与细胞内血红素的损失有关。我们进一步证实，Cu 抑制了血红素生物合成途径。我们提出，在 Cu 胁迫下产生血红素的能力受损会导致参与关键过程（如各种活性氧和氮物种的解毒以及需氧呼吸）的血红素蛋白无法激活。其影响将是细胞生物化学的全面破坏和 Cu 毒性的放大。
