Devising Novel Therapeutic Strategies to Tackle Tuberculosis

For generations, a devastating lung disease has ravaged communities, killing adults and children alike. Known as consumption or white death, tuberculosis (TB) results from infection with the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Despite antibiotics, TB remains a major global health threat, one that Jim Sun, a cellular microbiologist at the University of British Columbia (UBC), aims to eliminate. Sun’s team investigates how Mtb manipulates host macrophages and develops innovative therapies to fight this longstanding threat.

How did you get interested in science?

I always did well in science, but I did not develop a true interest in the subject until my research experience after completing my bachelor’s degree in biochemistry. I was lucky to get an opportunity to join a laboratory that worked on TB research at the Faculty of Medicine of UBC. I did not know much about TB or any other infectious disease when I started, but Mtb fascinated me because of its resilience. The microbe has spread through the human population for millennia. Unlike the many accidental pathogens, Mtb is a true human pathogen, and TB causes over a million deaths every year. While we have antibiotics to use as treatment, drug resistance is a major problem. Since the 1970s, physicians have prescribed antibiotic cocktails for patients with TB to help prevent resistance from emerging. However, it takes six months of treatment for drug-sensitive Mtb and up to two years for multidrug-resistant Mtb. Additionally, patients must comply with the strict treatment regimens, or else the bacterium is more likely to develop resistance. Further complicating matters, Mtb can remain dormant for long periods and then reactivate when the immune system becomes weakened. This nonreplicating state is very challenging to treat. My curiosity about this deadly pathogen and the search for new ways to combat it continues to drive my interest in this intriguing infectious disease.

What therapeutic strategies are your group pursuing?

My team is working on two key therapeutic approaches. The more traditional effort focuses on discovering new antibiotics. Over the last 60 years, regulatory agencies have approved only a few structurally novel classes of antibacterial drugs. We hope to expand the pipeline by identifying antibiotics with novel mechanisms of action, which will help avoid cross-resistance with existing drugs.

The other approach involves what we call host-directed therapies (HDTs), a concept similar to cancer immunotherapy. Instead of directly targeting the bacterium, we aim to reprogram macrophages to more effectively kill Mtb. The advantage of this strategy is that it is much harder for the pathogen to develop resistance because there is no selective pressure on Mtb itself. By combining HDTs with traditional antibiotics, physicians can achieve the best of both worlds and potentially shorten treatment by clearing the bacterium more quickly.

What exciting discoveries has your team uncovered in the search for new TB treatments?

In preliminary experiments, we identified a host phosphatase, PPM1A, as a promising HDT target. A previous study suggested that sanguinarine from the bloodroot plant could inhibit the phosphatase’s activity, but the alkaloid’s cytotoxicity limited its translational potential. Collaborating with chemists in China, we generated hundreds of sanguinarine derivatives.¹ One exhibited no toxicity in cell culture and mouse models while reducing their bacterial burden post-infection. These results were surprising because the pharmaceutical industry traditionally considered phosphatases undruggable. However, that sentiment is now changing.

In a serendipitous discovery, another sanguinarine derivative showed direct antibacterial activity, effectively killing multiple drug-resistant clinical strains and inhibiting the growth of nonreplicating Mtb.² We are quite excited about this compound and are now investigating its mechanism.

What has been the most rewarding aspect of your career so far?

The most rewarding part of my career is seeing the trainees within my laboratory navigate challenges and ultimately succeed. While the laboratory publishes the papers and secures the grants under my name, it is the postdoctoral fellows, graduate students, and undergraduate students who drive this research forward. Some are now in medical school, employed by the Canadian government, or working for pharmaceutical companies across Canada and Europe. I think that if you succeed at helping your trainees grow, then your scientific accomplishments will follow.

This interview has been condensed and edited for clarity.