Nitrite modulates aminoglycoside tolerance by inhibiting cytochrome heme-copper oxidase in bacteria

Zhang, Yongting; Guo, Kailun; Quanfei, Meng; Gao, Haichun

doi:10.1038/s42003-020-0991-4

Cited by 12 publications

(22 citation statements)

References 45 publications

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“…The proteomic data show that the quantity of cyt bd is barely affected by the Fur loss. This concurs with the previous observations that there is no compensating production for cyt bd when cyt cbb 3 is depleted (Yin et al, 2016;Zhang et al, 2020). Nonetheless, activity of cyt bd is significantly impaired upon Fur inactivation, evidenced by increased susceptibility to nitrite (Fu et al, 2013;Meng et al, 2018b;Zhang et al, 2020).…”

Section: Discussionsupporting

confidence: 92%

Free Rather Than Total Iron Content Is Critically Linked to the Fur Physiology in Shewanella oneidensis

et al. 2020

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Ferric uptake regulator (Fur) is a transcriptional regulator playing a central role in iron homeostasis of many bacteria, and Fur inactivation commonly results in pleiotropic phenotypes. In Shewanella oneidensis, a representative of dissimilatory metal-reducing γ-proteobacteria capable of respiring a variety of chemicals as electron acceptors (EAs), Fur loss substantially impairs respiration. However, to date the mechanism underlying the physiological phenomenon remains obscure. This investigation reveals that Fur loss compromises activity of iron proteins requiring biosynthetic processes for their iron cofactors, heme in particular. We then show that S. oneidensis Fur is critical for maintaining heme homeostasis by affecting both its biosynthesis and decomposition of the molecule. Intriguingly, the abundance of iron-containing proteins controlled by H2O2-responding regulator OxyR increases in the fur mutant because the Fur loss activates OxyR. By comparing suppression of membrane-impermeable, membrane-permeable, and intracellular-only iron chelators on heme deficiency and elevated H2O2 resistance, our data suggest that the elevation of the free iron content by the Fur loss is likely to be the predominant factor for the Fur physiology. Overall, these results provide circumstantial evidence that Fur inactivation disturbs bacterial iron homeostasis by altering transcription of its regulon members, through which many physiological processes, such as respiration and oxidative stress response, are transformed.

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Section: Discussionsupporting

confidence: 92%

Free Rather Than Total Iron Content Is Critically Linked to the Fur Physiology in Shewanella oneidensis

et al. 2020

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“…Further investigations into the NO-independent impacts of nitrite on HCOs have demonstrated that the essence of nitrite inhibition is proton translocation [153][154][155][156]. In P. aeruginosa, nitrite could not only prevent biofilm formation on the apical surface of airway epithelial cells but also modulate susceptibility to aminoglycosides by inhibiting bacterial respiration and oxygen uptake [157][158][159].…”

Section: Hcos Are Primary Targets Of Nitrite But Not No In Vivomentioning

confidence: 99%

Complex Interplay of Heme-Copper Oxidases with Nitrite and Nitric Oxide

Chen

Xie

Huang

et al. 2022

IJMS

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Nitrite and nitric oxide (NO), two active and critical nitrogen oxides linking nitrate to dinitrogen gas in the broad nitrogen biogeochemical cycle, are capable of interacting with redox-sensitive proteins. The interactions of both with heme-copper oxidases (HCOs) serve as the foundation not only for the enzymatic interconversion of nitrogen oxides but also for the inhibitory activity. From extensive studies, we now know that NO interacts with HCOs in a rapid and reversible manner, either competing with oxygen or not. During interconversion, a partially reduced heme/copper center reduces the nitrite ion, producing NO with the heme serving as the reductant and the cupric ion providing a Lewis acid interaction with nitrite. The interaction may lead to the formation of either a relatively stable nitrosyl-derivative of the enzyme reduced or a more labile nitrite-derivative of the enzyme oxidized through two different pathways, resulting in enzyme inhibition. Although nitrite and NO show similar biochemical properties, a growing body of evidence suggests that they are largely treated as distinct molecules by bacterial cells. NO seemingly interacts with all hemoproteins indiscriminately, whereas nitrite shows high specificity to HCOs. Moreover, as biologically active molecules and signal molecules, nitrite and NO directly affect the activity of different enzymes and are perceived by completely different sensing systems, respectively, through which they are linked to different biological processes. Further attempts to reconcile this apparent contradiction could open up possible avenues for the application of these nitrogen oxides in a variety of fields, the pharmaceutical industry in particular.

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“…[49] Additionally, the cyt aa 3 type of HCOs, such as ones from B. subtilis and S. aureus, were consistently found to be hypersensitive to nitrite. [47,50] Although cyt bd as hemoproteins are also susceptible to nitrite and NO revealed in early studies, [20] multiple lines of evidence support that HCOs are specific and most crucial targets of nitrite rather than of NO. Despite the hypersensitivity to nitrite, the S. oneidensis bd-deficient strain and the wild-type are indistinguishable from each other in their resistance to NO provided cyts c are produced at similar levels.…”

Section: Bacterial Targets Of Nitrite Revealed In Living Cellsmentioning

confidence: 99%

“…[51a] Indeed, in a variety of bacteria, including E. coli, P. aeruginosa, S. aureus, and B. subtilis, the NO-independent bacteriostasis of nitrite is attributable to inhibition of respiration. [50]…”

Section: Bacterial Targets Of Nitrite Revealed In Living Cellsmentioning

confidence: 99%

“…As HCOs are hypersensitive to nitrite, cyt bd confers a variety of bacteria nitrite resistance during aerobiosis. [47,50] Another example is bacterial aconitases, which are genetically distinct enzymes classified as A (AcnA) and B (AcnB). [74] While AcnB, which is sensitive to modification by hydrogen peroxide and NO, serves as the housekeeping isozyme for growth under normal conditions, AcnA as in E. coli is induced under various stressful conditions to function (Gardner et al, 1997;Varghese et al, 2003).…”

Section: Protection Systems For Nitrite and No Are Different In Bacteriamentioning

confidence: 99%

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Physiological Roles of Nitrite and Nitric Oxide in Bacteria: Similar Consequences from Distinct Cell Targets, Protection, and Sensing Systems

Guo

Gao

2021

Advanced Biology

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sodium nitrite) is currently in a phase 2b clinical trial as a drug for pulmonary hypertension treatment on the basis of the finding that it could be safely applied to reach millimolar concentrations in the airway surface liquid. [6] In the broad nitrogen biogeochemical cycle, nitrite serves as the central molecule linking nitrate (NO 3 − ) to dinitrogen gas (N 2 ) or ammonia (NH 3 ). [7] As a nitrogen oxo-anion, nitrite per se is crucial to life on earth because it participates in diverse key biological processes, especially in bacteria because they are renowned for their ability to carry out biological transformation of nitrite (Maia and Moura, 2014). Nitrite can be oxidized to nitrate or reduced to various nitrogen species such as nitric oxide (NO), nitrous oxide (N 2 O), N 2 , and NH 3 . [8] Although nitrite transformation is regarded as an effective means for detoxification, it brings out new threats. [7] Apart from an intermediate in the nitrogen cycle, NO, whose physiological concentrations are suggested to be up to ≈5 nM in cells, is a well-recognized bacteriostatic agent the same as nitrite. [9] It should be noted that concentrations of NO generated from nitrite reduction vary drastically in different bacteria, for example, less than 20 nM and up to 38 µM in cultures of two denitrifiers Paracoccus denitrificans and Agrobacterium tumefaciens, respectively. [10] In bacteria, a variety of enzymes are implicated in generation of NO from nitrite, and consistently, multiple enzymes contribute to transformation of NO to other nitrogen species for detoxification. [7,11] It is worth noting that in contrast to nitrite, whose transformation is exclusively conducted by enzymes involved in the nitrogen biogeochemical cycle, NO can be generated and scavenged by proteins outside the cycle, bacterial NO synthases (bNOSs) and flavohemoglobin Hmp, respectively. [12] Both nitrite and NO are bacteriostatic agents due to their ability to inhibit protein activity. In vitro studies show that nitrite and NO display similar, albeit not identical, biochemical properties, and therefore proteins susceptible to them are similar, mainly those containing redox-active centers such as heme, iron-sulfur clusters, mono-/di-nuclear iron, thiol, and so on. [13] Consistently, most of cellular targets identified in vivo are metabolic and respiratory enzymes depending on their redox-active centers for catalysis and/or oxi-reduction. [11] Despite this, cellular targets of nitrite and NO in any given bacterial species are Nitrite and nitric oxide (NO) are two active nitrogen oxides that display similar biochemical properties, especially when interacting with redox-sensitive proteins (i.e., hemoproteins), an observation serving as the foundation of the notion that the antibacterial effect of nitrite is largely attributed to NO formation. However, a growing body of evidence suggests that they are largely treated as distinct molecules by bacterial cells. Although both nitrite and NO are formed and decomposed by enzymes participating in the trans...

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Nitrite modulates aminoglycoside tolerance by inhibiting cytochrome heme-copper oxidase in bacteria

Cited by 12 publications

References 45 publications

Free Rather Than Total Iron Content Is Critically Linked to the Fur Physiology in Shewanella oneidensis

Free Rather Than Total Iron Content Is Critically Linked to the Fur Physiology in Shewanella oneidensis

Complex Interplay of Heme-Copper Oxidases with Nitrite and Nitric Oxide

Physiological Roles of Nitrite and Nitric Oxide in Bacteria: Similar Consequences from Distinct Cell Targets, Protection, and Sensing Systems

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