Crossroads: Chemical Tools for Discovering New Tuberculosis Therapies

Crossroads: Chemical Tools for Discovering New Tuberculosis Therapies


I’m Brett Babin from the Department of
Pathology at Stanford University. And I’ve been working with the long-term
goal to develop new therapeutics to treat tuberculosis. So, in many ways
tuberculosis, or TB, is a forgotten disease. One hundred years ago, TB killed one in seven people in the United States and Europe. But the introduction of antibiotic cures in the 1940s and 50s dramatically changed the world. This basically eliminated the disease in
the West and decreased incidence rates worldwide. So today TB is not really a disease that we in the United States need to worry about. But what you may not know is that TB remains a top-10 cause of death
worldwide. It’s the deadliest single infectious agent leading to approximately 2 million deaths each year. Also 1.7 billion people — nearly a quarter
of the world’s population — are infected with a latent form of the disease. And
they’re at risk to possibly develop active form of the disease at some point
in their lifetime. There are many barriers to the effective treatment of tuberculosis but one of the most concerning is the emerging threat of antibiotic resistance. The overuse and misuse of antibiotics around the world has led to the emergence of strains of bacteria that resist traditional therapies. So when patients are prescribed antibiotics in cases that they are not warranted or when patients fail to take their entire course of antibiotics, the bacteria that are exposed to the drug, but not killed by it, can evolve resistance. One promising approach to treat antibiotic-resistant bacteria is to develop new drugs that target new proteins, specifically those that are not targeted by existing therapies. Mycobacterium tuberculosis, the
causative agent of TB, is no exception. So, we don’t actually really know the
incidence rates of drug-resistant TB worldwide, but conservative estimates
estimate something like half a million new infections each year. That’s 5% of all new infections. As we lose our ability to treat TB with conventional antibiotics, a bad problem gets much worse. So I’ve been working to develop
potential new therapeutics to treat the disease. Compared to most bacteria, TB
has an especially complex cell envelope. This is the outer surface of the cell that interacts most closely with the host immune system. It enables TB to establish long-term infection and evade our body’s defenses. Mtb uses a class of
enzymes called hydrolases to build, maintain, and modify this cell wall or cell envelope. These enzymes are diverse. They’re important for infection and,
importantly, they’re not targeted by existing antibiotics. So I started this project by screening a library of small molecules that are designed to target hydrolase enzymes. I was excited to find a small handful of compounds that are able to kill Mtb in the lab. This preliminary discovery led to two main
questions: How do these compounds kill the bacterium? And, what is their potential for therapeutic use? Could we someday add these to our toolbox for treating the disease? To answer the first question, I used a chemical biology approach to identify the protein targets of the compounds. Using synthetic
chemistry, I created new variants of the compound molecules that feature chemical handles. These allow us to reach into the complex cellular environment and pull out the compounds and the proteins that they’re interacting with. By using this approach, I identified a few hydrolase enzymes that seemed to be targeted by
the drugs. This is exciting because it means we can move forward and use traditional biochemistry and genetic approaches to learn the function of
these enzymes, and to learn how these drugs are killing the bacterium. The second question about clinical relevance is in many ways a harder one. I first verified that these compounds do not kill human cells in the lab. This is critical because it means we can move forward and use infection models, cellular infection models, to test whether these compounds can kill Mtb in the context of
infection. But the road from the lab to the clinic is a long one. And we’ll next need to determine whether these compounds are effective in animal models of disease before moving forward. Even if these particular compounds do not end up being therapeutics, I’m excited to move forward with the project. The hydrolase enzymes that we identified have not been previously studied, and so we’re excited to learn more about what their functions are, how they modify the cell envelope, and how that’s important for infection. We also know that these enzymes have not been targeted previously by antibiotics. So we’re excited and hopeful that these drugs, or drugs like them, may be able to treat tuberculosis that is resistant to existing antibiotics.

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