The challenges of treating microbial infections are not new. For years, the medical community has struggled with bacteria becoming resistant to drugs and viruses evolving faster than we can generate vaccines. But the Covid-19 pandemic has presented a new set of challenges, showing us both what is possible in terms of speed of response and what we need to do better to prepare for the next one. A central lesson may 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 problem.
To this end, exciting work has been done around new strategies to complement standard care, including the antimicrobial effects of naturally occurring nitric oxide (NO) molecule with documented antiviral, antibiotic and antifungal properties. While the first therapeutic approval of NO in 1999 used its vasodilator effects for in-hospital treatment of blue baby syndrome (persistent pulmonary hypertension of the newborn), other research over the years has illustrated its potent antimicrobial effects, including a 2004 study. study shows its ability to neutralize the coronavirus of the time, SARS-CoV. Delivering the molecule in a sufficiently safe and convenient way (without the need for pressurized gas cylinders) and in the correct dose for daily use was the greater challenge.
Fortunately, a number of research groups are working on this very issue, developing new 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 easy-to-use methods for local delivery of NO. One of these involves storing and releasing NO from polymers for the treatment of viruses spread by direct contact, incl human papilloma virus (HPV) and the common childhood skin infection molluscum contagiosumas well as fungi and yeasts that infect the skin and nails. There is another group appreciated the antibacterial effects of NO released from biopolymers, finding that it kills a variety of bacteria and improves the susceptibility of antibiotic-resistant bacteria. An academic research group found that a platform of NO-releasing nanoparticles can significantly reduce the frequency of C. albicans infection and acceleration of healing in a mouse model of burn wounds.
Importantly, given the current pandemic and future viral pandemics that most experts believe we will see in our lifetime, local delivery of NO is also effective against airborne viruses, including SARS-CoV-2. one company studies a nasal spray that causes nasal cells to produce NO, with the hope that this 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 trials, including rapid viral load reduction in phase 3 study. Various research groups have also demonstrated the effectiveness of NO against a number of other respiratory viruses, including flurhinoviruses and RSV.
Part of what makes NO such a promising antimicrobial agent is that it works through several mechanisms of action (MOA). Against coronaviruses, these include blocking entry into the cells of the nasal passage and inactivating the virus through changes in the conformation of spike proteins and proteases, leading to a rapid reduction in viral load. The molecule also has several MOA in unicellular organisms, including DNA damage and inhibition of DNA repair, as well as lipid damage by lipid peroxidation, among others. These mechanisms make NO an effective antimicrobial agent capable of counteracting evolving variants and unlikely to lead to antimicrobial resistance (AMR). Topical NO also has a proven safety profile – a major advantage of topical application is that it lacks systemic absorption as measured by changes in methemoglobin or systemic vital signs such as blood pressure, so it is unlikely to be associated with systemic side effects or interactions in body.
Adding NO-based strategies to our existing armament has important real-world implications. As most countries transition from a ‘pandemic’ to an ‘endemic’ approach to Covid-19, the addition of new therapeutic tools for both prevention and treatment is critical. We are beginning to see some scientific and public interest in strategies beyond systemic vaccines, with the approval of antiviral drugs and increased research into nasal vaccines. But these agents have their drawbacks: oral antivirals can have “rebound effect”, and while nasal vaccines make logical sense, early try have not been effective and may have the same vulnerability to evolving variants as systemic vaccines.
In general, single-instrument treatment strategies for a single “bug” have limitations, which is why innovative complementary methods are so necessary. Nitric oxide can be an elegant and effective supplement that does not replace conventional methods, but works alongside them. As we prepare for the next pandemic, we will need tools to bridge the gap while vaccines are generated—while production of an mRNA vaccine is relatively rapid, many people can get sick and die during the waiting period. In addition to viral pandemics, AMR is one of the most pressing global health problems: predictions I guess that AMR could kill 10 million people a year by 2050 and cost $100 trillion globally. We are not ready to change that trajectory at this time. The antibacterial properties of nitric oxide can help reduce the overuse of antibiotics that has contributed to drug-resistant bacteria.
Overall, NO is a strong candidate to address many types of infections because its delivery is amenable to dosage-controlled therapeutic applications. The global health community as a whole needs more agents that are effective and safe for the population, including the elderly, children and immunocompromised individuals, and are easily transported and stored. Although more work remains to be done, current research into novel NO delivery platforms is extremely promising. We hope to see the molecule play an increasingly prominent role in treatment and prevention strategies for common infections – and thereby help provide greater access to healthcare worldwide.
Photo: Olemedia, Getty Images