Nitric oxide for the prevention and treatment ofviral, bacterial,protozoalandfungalinfections.

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

doi:10.12688/f1000research.51270.1

Abstract

Although the antimicrobial potential of nitric oxide(NO)is widelypublished, 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 andS-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 (includingβ-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. Trialsshould test dietary inorganic nitrate forpre- or post-exposureprophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment ofmild-to-severe infections, including due to SARS-CoV-2(COVID-19). This review summarises the evidence base from in vitro, in vivoand early phase clinical studies of NO activity inviral, bacterial,protozoalandfungalinfections.

Highlights

Nitric oxide (NO), an inorganic molecule, is generated endogenously by prokaryotes and eukaryotes from L-arginine by a family of NO synthase enzymes (NOS; Table 1.1).1 In higher animals, it is generated by reduction of dietary and endogenous nitrate (NO3À) to nitrite (NO2À) and thence NO (Table 1.2)
We identified publications relating to the effect of 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

Nitric oxide (NO), an inorganic molecule, is generated endogenously by prokaryotes and eukaryotes from L-arginine by a family of NO synthase enzymes (NOS; Table 1.1). In higher animals, it is generated by reduction of dietary and endogenous nitrate (NO3À) to nitrite (NO2À) and thence NO (Table 1.2). Nitric oxide (NO), an inorganic molecule, is generated endogenously by prokaryotes and eukaryotes from L-arginine by a family of NO synthase enzymes (NOS; Table 1.1).. Nitric oxide (NO), an inorganic molecule, is generated endogenously by prokaryotes and eukaryotes from L-arginine by a family of NO synthase enzymes (NOS; Table 1.1).1 In higher animals, it is generated by reduction of dietary and endogenous nitrate (NO3À) to nitrite (NO2À) and thence NO (Table 1.2). 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. Underlying these processes, NO modulates multiple cell types including leucocytes, platelets, endothelial cells and smooth muscle cells, and neuronal, cardiac and renal function. NO interacts with mitochondrial respiration, activates metabolic regulatory pathways and reduces oxidative stress

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