Toppling the Empire of Tuberculosis

Throughout the course of human history, various empires have risen and fallen in their quests for domination: the vast Roman empire, the expeditions of Alexander the Great, and even the spread of “manifest destiny” across the North American continent are some examples that come to mind. Since the evolution of modern humans, however, a menacing, microscopic empire has also made its way across the globe, and to this day, it continues its power-hungry mission of wreaking havoc on humanity.

The emperor of this threat to our society is named Mycobacterium tuberculosis, and TB, the disease it produces, remains the leading cause of death from a single infectious disease worldwide, ending the lives of nearly 2 million people annually. How do we stop this terrible tyrant in its tracks? This herculean task is the ambition of my research and that of my colleagues in the laboratory of Dr. Kyu Rhee at Weill Cornell Medicine in New York City.

The analogy of a disease as a relentless emperor is not a novel concept; Dr. Siddhartha Mukherjee chronicled the history and progression of cancer in his wildly popular work “The Emperor of All Maladies,” published in 2010. I find this imagery equally appropriate for envisioning how we understand pathogenic microorganisms, especially M. tuberculosis, which has unique characteristics that make the infections it causes particularly difficult to treat.

If tuberculosis as a global health challenge is an evil empire, individual bacterial cells can be seen as fortresses housing the important participants that keep the empire up and running. Since the 1940s, modern science and medicine have developed strategies to attack these miniscule fortresses in order to keep the disease at bay. The most effective strategy we have is sending antibiotics—which we can visualize as knights in shining armor—into the castle, where they can disrupt the state of affairs and bring the empire crumbling down from within. Unfortunately, the guards of the fortress are highly observant and adaptable, and over time, they have become resistant to the methods the knights use to gain entry.

Luckily, TB researchers have been hard at work attempting to circumvent the problem of antibiotic resistance. They’ve been conducting surveillance missions of sorts: biomedical investigations to identify the key players that keep the castle operational and the leadership in charge of maintaining order. In doing so, some scientists have even come up with brand new knights in shining armor that use different strategies than their predecessors to take down the fortress. A crucial part of putting these fighters into action, however, is ensuring that they actually get inside the walls of the fortress, which are notoriously thick and difficult to infiltrate.

My work in the lab focuses on these new knights in shining armor and how well they are able to breach the defenses of the castle. We evaluate a variety of antibiotic molecules and observe which ones have the greatest potential to gain entry to the castle—and stay inside once they’ve gotten there—so they can hit the TB empire where it hurts. So far, prior lab members and I have tested nearly 80 different drug molecules, determining how well they access the interior of TB-causing bacteria and searching for patterns in the chemical characteristics of molecules that accumulate well. We have uncovered a few such patterns, and much to our surprise, they run counter to the assumptions that the TB research community has been working with for years.

My work in the lab focuses on these new knights in shining armor and how well they are able to breach the defenses of the castle.

For good reason, scientists who study these bacteria assumed that the antibiotic molecules that were easily able to scale the walls of the fortress and get inside would be the most effective. But because antibiotics are molecules that just follow the laws of nature and, unlike human knights, don’t know that they have a task to perform, the results of our research suggest that the ones that get inside most easily might also be the ones that sneak out most easily—which doesn’t give them much time to take out the emperor. These findings have the potential to shift TB drug development efforts toward the antibiotic molecules that tend to stick around longer, giving them a higher chance of completing their mission.

Finally, the discovery of this peculiar pattern begs a new question: if the antibiotics that accumulate most effectively within M. tuberculosis are not the ones that traverse the fortress walls with ease, how are they getting inside? We don’t yet know the answer, but one hypothesis is that there is a yet-to-be discovered secret passageway, a transport system or channel of sorts, that allows them to gain entry. I hope that my future work will help answer these questions, contributing to a better understanding of how M. tuberculosis operates and employing that knowledge to design better treatments for TB.

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