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Review
. 2021 Jul 5:10:536.
doi: 10.12688/f1000research.51270.2. eCollection 2021.

Nitric oxide for the prevention and treatment of viral, bacterial, protozoal and fungal infections

Philip M Bath  1   2 , Christopher M Coleman  3 , Adam L Gordon  4   5 , Wei Shen Lim  6 , Andrew J Webb  7
Affiliations
Review

Nitric oxide for the prevention and treatment of viral, bacterial, protozoal and fungal infections

Philip M Bath et al. F1000Res. .

Abstract

Although the antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses. Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite and S-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (including β-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts in vitro. Therapeutic effects have been seen in animal models in vivo, and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trials should test dietary inorganic nitrate for pre- or post-exposure prophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment of mild-to-severe infections, including due to SARS-CoV-2 (COVID-19). This review summarises the evidence base from in vitro, in vivo and early phase clinical studies of NO activity in viral, bacterial, protozoal and fungal infections.

Keywords: Bacteria; COVID-19; fungus; nitrate; nitric oxide; nitrite; protozoa; virus.

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Conflict of interest statement

Competing interests: PMB is Stroke Association Professor of Stroke Medicine and is a NIHR Emeritus Senior Investigator; he is chief investigator of the BEET-Winter and PROTECT-CH trials and was chief investigator of 6 trials of GTN in acute stroke; he has received honoraria as Chair of the Steering Committee for DiaMedica. AG is co-chief investigator of the PROTECT-CH trial. AJW holds shares in HeartBeet Ltd, which receives a royalty from James White Drinks Ltd, which manufactures active nitrate-containing and placebo nitrate-depleted beetroot juice used in clinical studies. All the authors are investigators in the BEET-Winter trial. The authors have no association with any of the companies mentioned in this review.

Figures

Figure 1.
Figure 1.. Schematic of concentration response curve for antimicrobial effects of nitric oxide.
  1. 1.

    Reduced eNOS-derived NO related to dietary insufficiency, older age, vascular disease

  2. 2.

    Normal eNOS-derived vascular NO

  3. 3.

    iNOS-derived NO or low/moderate dose exogenous NO source

  4. 4.

    iNOS-derived NO in septic shock or high dose exogenous NO source

See this image and copyright information in PMC

References

    1. Palmer RMJ, Ashton DS, Moncada S: Vascular endothelial cells synthesise nitric oxide from L-arginine. Nature. 1988;333(6174):664–6. 10.1038/333664a0 - DOI - PubMed
    1. Flam BR, Eichler DC, Solomonson LP: Endothelial nitric oxide production is tightly coupled to the citrulline-NO cycle. Nitric Oxide. 2007;17(3-4):115–21. - PubMed
    1. Bahadoran Z, Mirmiran P, Kashfi K, et al. : Endogenous flux of nitric oxide: Citrulline is preferred to Arginine. Acta Physiol (Oxf). 2021;231(3):e13572. - PubMed
    1. Bath PMW, Hassall DG, Gladwin A-M, et al. : Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb. 1991;11:254–60. 10.1161/01.atv.11.2.254 - DOI - PubMed
    1. Radomski MW, Palmer RMJ, Moncada S: Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet. 1987;ii:1057–8. 10.1016/s0140-6736(87)91481-4 - DOI - PubMed