It’s a global pandemic that’s killed millions, sickened many more and caused considerable economic damage. Highly prevalent, it’s spread through the air, often within households or crowded indoor environments. 

We’re not talking about Covid-19. We’re talking about tuberculosis. 

Tuberculosis (TB), which is caused by the Mycobacterium tuberculosis bacterium, has been infecting people for thousands of years. Fortunately, researchers are making strides in the fight against one of the world’s oldest and most devastating pandemics.

In their long-running collaboration with the global not-for-profit TB Alliance, Distinguished Professor Sir Bill Denny and Senior Research Fellow Hamish Sutherland have been part of a team that has succeeded in taking three new tuberculosis drugs to clinical trial – an amazing success rate that could potentially improve and perhaps save the lives of millions.

Although Covid-19 has killed more people in the last few years, TB has been the world’s deadliest infectious disease over the longer term. In 2020, about 10 million new patients fell ill with TB, while 1.5 million died – and numbers have been similar for years. 

Although New Zealand is considered a low-prevalence country, it still sees about 300 cases a year. Most patients come from higher-incidence countries, but New Zealand-born patients, like TB patients elsewhere, are more likely to be suffering from socio-economic deprivation. About half of the New Zealand-born patients in 2011-15 were Māori, making TB an equity issue.

Some countries in the Pacific have high rates of TB, particularly Papua New Guinea, Kiribati and the Marshall Islands. Papua New Guinea, considered by the World Health Organisation to have a high TB burden, has seen its incidence rate rise notably in the last decade.

Moreover, about one in four people in the world are thought to be infected without showing symptoms. While some people with latent TB never get sick, others develop active illness years or decades later. 

Active tuberculosis, if untreated, kills over half of patients within five years. Treatment, however, isn’t easy. 

In recent decades, pharmaceutical companies have not invested much into tuberculosis drug development because it is largely a disease of lower-income countries and the potential for profit is low. TB Alliance has stepped in to fill the gap. 

For over 20 years, TB Alliance, which is funded by a range of donors including governments and private organisations such as the Bill & Melinda Gates Foundation, has worked directly with research and development partners including the University of Auckland. Headquartered in New York City, its mission is to develop better, faster acting and affordable tuberculosis drugs.

Denny leads the longest-running academic collaboration with TB Alliance. In 2005, he and his team were working with a U.S. pharmaceutical company when one of its senior biologists suggested Denny get in touch with TB Alliance because his lab had worked on similar chemistry to its new project.

“I noted that seemed unlikely to work, but he said any such letter would go to the TB Alliance collaborations advisor for comment, and he was that person,” recalls Denny. “So UniServices funded a trip to New York, I presented, and we got a one-year initial contract that still funds five scientists here to this day.”

TB Alliance’s greatest success to date is the breakthrough drug regime, BPaL, which stands for its three dugs – bedaquiline, pretomanid and linezolid. The regime, approved by the U.S. Food and Drug Administration (FDA) in 2019, is the first to show significant efficacy in treating MDR-TB and XDR-TB. 

While significantly safer and more effective than the traditional regime, some of the BPaL drugs still carry important risks of side effects. Even before BPaL was approved, Denny’s team started working on “next generation” replacements for bedaquiline and pretomanid with the goal of finding alternatives with better pharmacological and safety properties.

A pretomanid alternative the Auckland team developed didn’t make it beyond Phase One clinical trial. However, Denny and his team have found two possible alternatives to bedaquiline. Their two new compounds, currently known by the none-too-catchy names of TBAJ-587 and TBAJ-876, appear in animal models to be safer and more effective than bedaquiline. 

TBAJ-587 and TBAJ-876 are currently in Phase One human clinical trials, so they’re largely out of the team’s hands. If one or both get through clinical trials, the better one could replace bedaquiline as a safer alternative in the BPaL regime.

Sutherland, who joined the team in 2007, says it’s important for him to know he’s “doing something that’s good for the world.” He also enjoys the challenge of the chemistry. 

Denny, Sutherland and their team aren’t done yet in their quest to better treat tuberculosis. Still working with TB Alliance, they’re in the early stages of work to target and inhibit other enzymes of the bacterium. 

“Any target we can go after, we will,” says Sutherland. “Drug resistance will be a driver forever, so we need to expand the material biologists and doctors have to target TB in all its forms.”