Micromolecular inhibitors of superoxide radicals

Background: Currently, there is a growing interest in new copper (Cu2+) heterocyclic coordination compounds (CC), isothiosemicarbazide derivates, which demonstrated multiple beneficial properties, but their effect on reactions with free radicals such as the superoxide radical has not been investigated. Material and methods: The action of new micromolecular complexes of copper (Cu2+) chloride and bromide with methyl n- (prop-2-en-1-yl) -2- (pyridin2-ylmethylidene) hydrazine carbimidothioate on capturing activity of the superoxide radical was determined by the spectrophotometric method in vitro experiments. Results: It was established that the micromolecular complexes of copper (II) chloride and bromide with methyl n-(prop-2-en-1-yl)-2-(pyridin-2- ylmethylidene) hydrazine carbimidothioate have been found to possess strong superoxide radical inhibitor properties when interacting with a superoxide radical. In addition to this, the IC50 of the studied compounds depends on the nature of the acid-ligand in the internal sphere of the complex and increases in the following sequence: Cl- –Br- . Conclusions: The established property of mentioned compounds is new, because their use as micromolecular inhibitors of superoxide radicals has not been described so far. The synthesized CC expand the arsenal of superoxide radical inhibitors with high biological activity. Their possible significance for the development of new treatment strategies for diseases associated with the overproduction of superoxide radicals is discussed.

Free spermidine evokes superoxide radicals that manifest toxicity

Spermidine and other polyamines alleviate oxidative stress, yet excess spermidine seems toxic to Escherichia coli unless it is neutralized by SpeG, an enzyme for the spermidine N-acetyl transferase function. Besides, a specific mechanism of SpeG function conferring pathogenic fitness to Staphylococcus aureus USA300 strain is unknown. Here, we provide evidence that although spermidine mitigates oxidative stress by lowering hydroxyl radical and hydrogen peroxide levels, excess of it simultaneously triggers the production of superoxide radicals, thereby causing toxicity in the E. coli ΔspeG strain as well as naturally SpeG-deficient S. aureus RN4220 strain. However, wild-type E. coli and S. aureus USA300 with a horizontally-acquired speG gene tolerate applied exogenous spermidine stress. Furthermore, we demonstrate that while RNA-bound spermidine inhibits iron oxidation, free spermidine interacts and oxidizes the iron to evoke superoxide radicals directly. Superoxide radicals thus generated, further affects redox balance and iron homeostasis. Since iron acquisition and metabolism in the host tissues is a challenging task for S. aureus, the current findings helped us explain that the evolutionary gain of SpeG function by S. aureus USA300 strain allows it to neutralize exogenous spermidine- and spermine-mediated toxicity towards iron metabolism inside the host tissues.

Membrane depolarization kills dormant Bacillus subtilis cells by generating a lethal dose of ROS

The bactericidal activity of several commonly used antibiotics have been shown to partially rely on the production of reactive oxygen species (ROS). Bacterial persister cells, an important cause of recurring infections, are tolerant to these antibiotics because they are in a dormant state. However, even dormant cells must maintain a membrane potential. Here we used Bacillus subtilis as model system to study the effect of membrane depolarization on dormant cells. Surprisingly, we found that membrane depolarization also leads to ROS production. In contrast to previous studies, this does not require the Fenton reaction and results primarily in superoxide radicals. Genetic analysis revealed that Rieske factor QcrA, the iron-sulfur subunit of complex III, is a primary source of superoxide radicals. Interestingly, the membrane distribution of QcrA changed upon membrane depolarization, suggesting a dissociation of complex III. Our data reveal an alternative mechanism by which antibiotics can cause lethal ROS levels, and may partially explain why membrane-targeting antibiotics are effective in eliminating persisters.

Xanthine Oxidase-Induced Inflammatory Responses in Respiratory Epithelial Cells: A Review in Immunopathology of COVID-19

Xanthine oxidase (XO) is an enzyme that catalyzes the production of uric acid and superoxide radicals from purine bases: hypoxanthine and xanthine and is also expressed in respiratory epithelial cells. Uric acid, which is also considered a danger associated molecule pattern (DAMP), could trigger a series of inflammatory responses by activating the inflammasome complex path and NF-κB within the endothelial cells and by inducing proinflammatory cytokine release. Concurrently, XO also converts the superoxide radicals into hydroxyl radicals that further induce inflammatory responses. These conditions will ultimately sum up a hyperinflammation condition commonly dubbed as cytokine storm syndrome (CSS). The expression of proinflammatory cytokines and neutrophil chemokines may be reduced by XO inhibitor, as observed in human respiratory syncytial virus (HRSV)-infected A549 cells. Our review emphasizes that XO may have an essential role as an anti-inflammation therapy for respiratory viral infection, including coronavirus disease 2019 (COVID-19).