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

Philip M Bath,Adam L Gordon,Christopher M Coleman,Wei Shen Lim,Andrew J Webb

doi:10.12688/f1000research.51270.2

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.

Highlights

The antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically
We identified publications relating to the effect of Nitric oxide (NO) on viruses, bacteria, protozoa and fungi/yeasts from searches of our own reference libraries, PubMed and Google, and reference lists given in earlier reviews and commentaries
There is a large volume of literature spanning the last 30+ years demonstrating that NO has potent in vitro antimicrobial effects on a wide variety of viruses, bacteria, protozoa, fungi and yeasts; these are supported by a modest number of in vivo studies

Summary

Introduction

The antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically. Any further responses from the reviewers can be found at the end of the article Introduction Nitric oxide (NO), an inorganic molecule, is generated endogenously by prokaryotes and eukaryotes from L-arginine and L-citrulline by a family of NO synthase enzymes (NOS; Table 1.1, Table 1.2).. Any further responses from the reviewers can be found at the end of the article Introduction Nitric oxide (NO), an inorganic molecule, is generated endogenously by prokaryotes and eukaryotes from L-arginine and L-citrulline by a family of NO synthase enzymes (NOS; Table 1.1, Table 1.2).1-3 In higher animals, it is generated by reduction of dietary and endogenous nitrate (NO3À) to nitrite (NO2À) and thence NO (Table 1.3). NO is a pleiotropic signalling molecule involved in vascular, neuronal and metabolic regulation and has multiple physiological effects including lowering blood pressure, increasing exercise performance, and reversing metabolic syndrome. NO interacts with mitochondrial respiration, activates metabolic regulatory pathways and reduces oxidative stress

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