SARANAC LAKE — A doctor at the Trudeau Institute has received a $1.4 million grant to study improved treatment for tuberculosis.
Exactly 140 years after Edward Livingston Trudeau founded the research institute in Saranac Lake, the first in the country for the study of tuberculosis, researchers there are still studying the deadly infectious disease which kills between 1 and 2 million people each year.
William Reiley, who is also Trudeau Institute’s president and director, said the $1,437,261 grant from the Bill and Melinda Gates Foundation will fund studies evaluating nicotinamide’s ability to be used in conjunction with other compounds currently in clinical use to shorten the treatment of tuberculosis.
The 18-month project titled “Nicotinamide in vivo mouse studies” has already started. The focus is on using nicotinamide as an “add-on drug” to an already existing regimen meant to shorten treatment of tuberculosis. Reiley said researchers have turned their attention to nicotinamide recently because of the rediscovery of research from the 1950s on it.
“Lo and behold, it’s actually, seemingly, a pretty potent compound,” he said.
Nicotinamide is the water-soluble form of vitamin B3, meaning it dissolves in water. It has nothing to do with nicotine, the addictive compound in cigarettes, Reiley clarified.
Nicotinamide is cheap, safe and naturally produced by the body. It is already approved for use by the federal Food and Drug Administration.
“What better drug than a vitamin?” Reiley asked.
The research
One of the major problems that tuberculosis patients around the world face is that the treatment is very long — 6 to 9 months of taking antibiotics.
Sometimes, when people finish their treatment and bacteria is not detected anymore by modern equipment, it can still come back and infect the person again. This happens in around 5% of patents with drug-susceptible tuberculosis, Reiley said.
“A lot of times, the severity is actually worse than when they first started,” he said.
They are also studying if nicotinamide can prevent the bacteria from relapsing.
Almost all treatments have side effects. This is especially true in tuberculosis treatments, Reiley said, which are much longer than treatments for other infectious diseases. Usually, someone might spend days or weeks taking antibiotics to deal with an infection. With tuberculosis, they spend months. This extended treatment can damage liver and kidney function. If nicotinamide can shorten these treatments, it can reduce the risks and side effects.
The current tuberculosis treatment is made up of antibiotics isoniazid, rifampicin, pyrazinamide and ethambutol. But drug-resistant forms of tuberculosis have emerged since the start of antibiotic treatment. In these cases, medical professionals also can use antibiotics moxifloxacin, bedaquiline and linezolid, depending on the mutations.
This second batch of drugs for treating tuberculosis strains resistant to traditional treatment is the regimen Riley said they are pairing nicotinamide with.
“The purpose of putting this with second and third line regiments is to help combat the ongoing need for new compounds and therapies, especially those that can tackle the ever-growing levels of resistant bacteria,” Reiley wrote in an email.
The research will use two different mouse models. Each imitates the human disease in a different fashion.
The research essentially involves giving a mouse tuberculosis then using nicotinamide and other existing treatment to see if it’s effective at clearing out the bacteria.
The first model will look at bacteria which resides in the cells and has a high bacterial burden, making it difficult to clear with clinical drugs. The second model will look at intracellular and extracellular bacteria, including ones which develop granuloma structures, the hallmark appearance of tuberculosis which causes coughing.
“This second model is important as it allows for us to evaluate how compounds can penetrate this (granuloma) structure as not all compounds are capable of entering this structure and able to work on the bacteria residing inside of these structures,” Reiley wrote in an email.
If nicotinamide proves effective at clearing bacteria, the next step will be to look at the “mechanism of action” nicotinamide is using, to learn more about how it works. The main question they’ll be looking to answer is if the treatment is helping the host’s immune system attack bacteria.
“We know that the compound is actively working on the bacteria,” Reiley said in an email, “though the mechanism of action is unclear. But there are reports in the literature that nicotinamide (can) boost immune function.”
Current tuberculosis therapies only target the bacteria.
“This is why we are interested in exploring therapies that can target the host response,” Reiley said in an email. “The fact that nicotinamide may do both is extremely exciting to us and why we are studying it.”
“Dirty little secret”
Reiley is passionate about tuberculosis research.
With this grant, he said he’s “excited and proud” to continue the legacy in the fight against tuberculosis at Trudeau Institute, which is named for Edward Livingston Trudeau, the famed 19th-century doctor who pioneered research on tuberculosis in Saranac Lake.
Reiley hopes if he was sitting with Trudeau, they’d have great talks about the disease. He laughs at first, thinking about this, but then gets serious.
“It’s sad, really,” he said. “Think about it, 140 years that we’ve been still working on this pathogen.”
With all the advancements in technology and medicine in the 20th and 21st centuries, a real cure for tuberculosis still eludes scientists.
“TB remains a major global health concern as the leading cause of death attributable to a single infectious disease,” according to a Trudeau Institute news release. “It is estimated that nearly 1 in 3 people across the globe are infected by M. tuberculosis and the World Health Organization reported 1.25 million deaths from this disease in 2023.”
Reiley said, this year, tuberculosis-related deaths are on course to hit 1.8 million.
It is still the number-one cause of infectious disease death globally, only surpassed by SARS-CoV-2 during the height of the coronavirus pandemic. Tuberculosis is not perceived in this way in the U.S., Reiley said, but it is a pandemic of its own.
While around 1 in 3 people globally contract the disease at some point in their life, only around 10% have an “active disease,” he said — the coughing and sickness associated with tuberculosis.
Reiley said “latent infection,” when someone is asymptomatic, is really interesting and needs more study. Most study is focused on actively infected people.
When someone has a latent infection, they could have range of contagiousness. Tuberculosis spreads through coughing and sneezing. But some people infected with the disease have no bacteria at all. Their immune system allows them to get rid of pathogens.
However, these people could be fine for years, until something in their body changes, usually brought on by taking immunosupressive drugs for other medical care or contracting HIV.
Tuberculosis infection is more common in the developing world. The U.S. has had easy access to antibiotics for decades now, but better access to treatment is costly. Things like wars, regionality or access to medical care can cause more death from tuberculosis.
Also, Reiley said the American standard of a single-family home leads to less spread, compared to the multi-generational family home typical in other places in the world.
But still, he said tuberculosis is more common than people realize in urban areas of America. This is the “dirty little secret that no one really talks about,” he said.
The Trudeau Institute studies a multitude of infectious diseases. Recently, it also received a $1 million federal grant, along with local biotechnology company Ampersand Biosciences, to research the flu in ferrets. A story about this research will be in the Enterprise next week.