The challenges in treating microbial infections aren’t new. For years, the medical community has grappled with bacteria becoming drug-resistant and viruses evolving faster than we can generate vaccines. But the Covid-19 pandemic presented a new set of challenges, showing us both what’s possible in terms of speed of response and what we need to do better to prepare for the next one. A central lesson might be that we need to move away from the idea of managing a single “bug” with a single tool – it will take a collection of approaches working in concert to fully wrap our arms around a given problem.
To this end, there’s been exciting work around new strategies to supplement standard care, including the antimicrobial effects of nitric oxide (NO), a naturally occurring molecule with documented antiviral, antibiotic, and antifungal properties. While the first therapeutic approval of NO in 1999 leveraged its vasodilatory effects for hospital treatment of blue baby syndrome (persistent pulmonary hypertension of the newborn), another body of research over the years has illustrated its robust antimicrobial effects, including a 2004 study showing its ability to neutralize the coronavirus of the time, SARS-CoV. Delivering the molecule in a safe and convenient enough route (without the need for pressurized gas cylinders) and at the right dose for everyday use had been the larger challenge.
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Luckily, a number of research groups have been working on this very issue, developing novel methods to generate NO for new therapeutic applications. Some have developed “tankless” systems, which use electricity to generate inhaled NO for use in hospitals or homes. Others are working on user-friendly methods to deliver NO topically. One of these involves storing and releasing NO from polymers to treat viruses spread by direct contact, including human papillomavirus (HPV) and the common children’s skin infection molluscum contagiosum, as well as fungi and yeasts that infect skin and nails. Another group has evaluated the antibacterial effects of NO released from biopolymers, finding that it kills a variety of bacteria and improves susceptibility in antibiotic-resistant bacteria. One academic research group found that an NO-releasing nanoparticle platform can greatly reduce the incidence of C. albicans infection and accelerate healing in a mouse model of burn wounds.
Importantly, given the current pandemic and the future viral pandemics most experts believe we’ll see in our lifetimes, topical NO delivery also has also been effective against airborne viruses, including SARS-CoV-2. One company is researching a nasal spray that induces nasal cells to produce NO, in the hopes that it may serve as a prophylactic. Our own group has developed a compact delivery system that generates NO right when the user activates it. One of its applications, an NO-releasing nasal spray, has shown promise against SARS-CoV-2 and its variants in both laboratory and clinical studies, including rapid viral load reduction in a Phase 3 study. Various research groups have also demonstrated the effectiveness of NO against a number of other respiratory viruses, including flu, rhinoviruses, and RSV.
Part of what makes NO such a promising antimicrobial is that it works through several mechanisms of action (MOA). Against coronaviruses, these include blockage of entry into nasal passage cells and inactivation of the virus via conformation changes to the spike proteins and proteases, which lead to rapid reduction in viral load. The molecule also has several MOA in single-celled organisms, including DNA damage and inhibition of DNA repair, as well as lipid damage via lipid peroxidation, among others. These mechanisms make NO an effective antimicrobial, able to stand up to evolving variants and unlikely to lead to antimicrobial resistance (AMR). Topical NO also has a demonstrated safety profile – a key benefit of topical use is that it lacks systemic absorption, as measured by changes in methemoglobin or systemic vital signs like blood pressure, so it’s unlikely to be associated with systemic side effects or interactions in the body.
The addition of NO-based strategies to our existing armamentarium has important real-world implications. With most countries transitioning from “pandemic” to “endemic” approaches to Covid-19, adding new therapeutic tools for both prevention and treatment is critical. We’re starting to see some scientific and public interest in strategies beyond systemic vaccines, with the approval of antiviral medications and increased research into nasal vaccines. But these tools have their own drawbacks: oral antivirals can have a “rebound effect,” and while nasal vaccines make sense logically, early attempts haven’t been effective and may have the same vulnerabilities to evolving variants that systemic vaccines do.
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Generally, strategies to treat a single “bug” with a single tool have limitations, which is why innovative adjunct methods are so greatly needed. Nitric oxide can be an elegant and effective addition, not to replace conventional methods, but to work alongside them. As we prepare for the next pandemic, we’ll need tools to bridge the gap while vaccines are being generated – while mRNA vaccine production is relatively fast, many people can get sick and die during the waiting period. In addition to viral pandemics, AMR is one of the most urgent global health concerns: Projections suggest that AMR may kill 10 million people annually by the year 2050 and cost $100 trillion globally. At present, we are poorly poised to change that trajectory. Nitric oxide’s antibacterial properties could help reduce the excessive use of antibiotics that has contributed to drug-resistant bacteria.
All in all, NO is a strong candidate to help address many types of infection, as its delivery is adaptable across therapeutic applications with controlled dosing. The global healthcare community generally needs more agents that are effective and safe across populations, including the elderly, children, and immunocompromised individuals, and are easily transported and stored. While more work needs to be done, the current research into new delivery platforms for NO is extremely promising. We hope to see the molecule play an increasingly prominent role in treatment and prevention strategies for common infections – and in so doing help provide greater access to healthcare globally.
Photo: Olemedia, Getty Images
Gilly Regev (CEO) & Chris Miller (CSO) are the Co-Founders of Canadian R&D company, SaNOtize Research and Development Corp. Regev earned her PhD in Biochemistry at the Hebrew University of Jerusalem and Miller originally a respiratory therapist, earned his PhD in Experimental Medicine from the University of British Colombia and holds BA in Health Management. Both are exceptional leaders with strong academic foundations, are well published, have biotech start-up experience with decades of expertise in harnessing the core antimicrobial technology, nitric oxide. Since SaNOtize’s 2017 launch, they have successfully led the company from the laboratory, through the clinical regulatory gauntlet, formulation and scaled manufacturing hurdles to the retail shelf. Their lead product, Nitric Oxide Nasal Spray (NONS™), is approved for sale in more than 10 countries and they are now in discussions with regulatory authorities in both Canada and the U.S.
