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

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.

Dietary nitrate supplementation for preventing and reducing the severity of winter infections, including COVID-19, in care homes (BEET-Winter): a randomised placebo-controlled feasibility trial

“…Nitric oxide (NO) possesses broad-spectrum antimicrobial activity with substantial in vitro and some in vivo data demonstrating anti-viral, bacterial, protozoal and fungi/yeast activity [5]. The antimicrobial effects of NO and derivative ions such as peroxynitrite are mediated by effects on RNA/ DNA and protein conformation [5].…”

“…Nitric oxide (NO) possesses broad-spectrum antimicrobial activity with substantial in vitro and some in vivo data demonstrating anti-viral, bacterial, protozoal and fungi/yeast activity [5]. The antimicrobial effects of NO and derivative ions such as peroxynitrite are mediated by effects on RNA/ DNA and protein conformation [5]. NO also improves organ blood supply and has pro-endothelial and anti-inflammatory and antithrombotic effects mediated through anti-leucocyte and anti-platelet activity [6], and these may also contribute to its antimicrobial effects.…”

“…A recent human trial showed that a NO-nasal spray accelerated nasal SARS-CoV-2 viral clearance [11]. Endogenous NO is made from dietary amino acids (L-arginine and L-citrulline) and nitrate [5]. Phase II-equivalent clinical trials have supported anti-microbial effects of NO made from acidified nitrite on cutaneous viral and bacterial infections, dietary nitrate on oral bacteria, and NO gas against some respiratory viral infections [5].…”

“…Endogenous NO is made from dietary amino acids (L-arginine and L-citrulline) and nitrate [5]. Phase II-equivalent clinical trials have supported anti-microbial effects of NO made from acidified nitrite on cutaneous viral and bacterial infections, dietary nitrate on oral bacteria, and NO gas against some respiratory viral infections [5]. Further, NO has been shown to improve exercise performance and cognition in older people [12], potential benefits of relevance to care home residents.…”

“…RSV) and vaccinations may need to be combined with chemoprophylaxis for effective prevention, especially in a population where immunosenescence is normal [13,14]. So, NO substrates and donors may be particularly relevant due to their potential generic antimicrobial effects, especially since resistance against NO appears to be rare [5] in contrast to that occurring with many specific antimicrobial agents [1].…”