Sodium Nitrite Inhibits Killing of Pseudomonas aeruginosa Biofilms by Ciprofloxacin

Zemke, Anna C.; Kocak, Brian R.; Bomberger, Jennifer M.

doi:10.1128/aac.00448-16

Cited by 14 publications

(13 citation statements)

References 12 publications

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“…In such conditions, antibiotic efficacy is linked to respiratory activity; for example, deletion of the cytochrome oxidases, which reduces respiration, inhibits drug lethality [34], while deletion of ATP synthase subunits, which increases respiration, enhances lethality [34,69]. Similarly, respiratory suppression by nitrite also inhibits antibiotic killing [70]. Under anoxia, nitrate frequently participates in anaerobic respiration as the terminal electron acceptor and can potentiate antibiotic killing [33]; it is not yet known if nitrate and other terminal electron acceptors also generate toxic metabolic byproducts that contribute to antibiotic death processes.…”

Section: Environmental Factorsmentioning

confidence: 99%

Antibiotic efficacy — context matters

Yang

Bening

Collins

2017

Current Opinion in Microbiology

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Antibiotic lethality is a complex physiological process, sensitive to external cues. Recent advances using systems approaches have revealed how events downstream of primary target inhibition actively participate in antibiotic death processes. In particular, altered metabolism, translational stress and DNA damage each contribute to antibiotic-induced cell death. Moreover, environmental factors such as oxygen availability, extracellular metabolites, population heterogeneity and multidrug contexts alter antibiotic efficacy by impacting bacterial metabolism and stress responses. Here we review recent studies on antibiotic efficacy and highlight insights gained on the involvement of cellular respiration, redox stress and altered metabolism in antibiotic lethality. We discuss the complexity found in natural environments and highlight knowledge gaps in antibiotic lethality that may be addressed using systems approaches.

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Section: Environmental Factorsmentioning

confidence: 99%

Antibiotic efficacy — context matters

Yang

Bening

Collins

2017

Current Opinion in Microbiology

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“…The study has demonstrated that nitrite could be safely applied to reach millimolar concentrations in the airway surface liquid, paving the road for the agent to be a previously unidentified antimicrobial therapy. Nitrite has also been found to be either cooperative or antagonistic when used in combination with antibiotics in Pseudomonas aeruginosa 8,10,11 . These effects are a result of the bacteriostatic action, which does not require NO as an intermediate 1 .…”

mentioning

confidence: 99%

“…Tolerance induced by nitrite to aminoglycosides and Cip is proposed to be attributed to impaired respiration (oxygen consumption rate, hereafter referred to as respiration) given similar effects of other respiratory inhibitors, such as cyanide and carbonyl cyanide m-chlorophenylhydrazone (CCCP) 10,11 . As nitrite is bacteriostatic, this proposal is in perfect agreement with the recent report that antibiotic efficacy is linked to bacterial cellular respiration 13 .…”

mentioning

confidence: 99%

“…However, given that aminoglycosides have long been proposed to depend on proton motive force (PMF) for uptake 14 , it is possible that nitrite-mediated aminoglycoside tolerance may not be a direct result of reduced respiration. Unfortunately, in most, if not all, of these previous studies [10][11][12][13] , respiration is virtually an equivalent of PMF, because the observations were from the proton gradient inhibitors, with CCCP being the most commonly used one. Thus, although reduced respiration likely compromises PMF formation, the direct evidence is lacking.…”

mentioning

confidence: 99%

“…Thus, although reduced respiration likely compromises PMF formation, the direct evidence is lacking. More importantly, despite these findings, the antimicrobial mechanisms of nitrite, especially those through which respiration and/or PMF are impaired, is only partially understood 11 .…”

mentioning

confidence: 99%

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

et al. 2020

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As a bacteriostatic agent, nitrite has been used in food preservation for centuries. When used in combination with antibiotics, nitrite is reported to work either cooperatively or antagonistically. However, the mechanism underlying these effects remains largely unknown. Here we show that nitrite mediates tolerance to aminoglycosides in both Gram-negative and Gram-positive bacteria, but has little interaction with other types of antibiotics. Nitrite directly and mainly inhibits cytochrome heme-copper oxidases (HCOs), and by doing so, the membrane potential is compromised, blocking uptake of aminoglycosides. In contrast, reduced respiration (oxygen consumption rate) resulting from nitrite inhibition is not critical for aminoglycoside tolerance. While our data indicate that nitrite is a promising antimicrobial agent targeting HCOs, cautions should be taken when used with other antibiotics, aminoglycosides in particular.

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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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Sodium Nitrite Inhibits Killing of Pseudomonas aeruginosa Biofilms by Ciprofloxacin

Cited by 14 publications

References 12 publications

Antibiotic efficacy — context matters

Antibiotic efficacy — context matters

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

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

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