Colorado State researchers breach the walls of M. tuberculosis

The lowly bacterium, Mycobacterium tuberculosis, has plagued mankind for thousands of years. An estimated one third of our human tribe still suffers from tuberculosis or TB. More than 2 million people die annually from the disease. The microbe lays waste to human lungs and passes easily from person to person. Sufferers cough, releasing a mist of infectious particles that grow actively in bodies weakened from poor nutrition and illness or lie dormant for years, time capsules of potential destruction. Since 1946, one or more antibiotics have served to keep TB at bay, but resistant strains and the spread of HIV has allowed M. tuberculosis to make a comeback. Microbiology researchers at Colorado State University claim a “eureka discovery” that provides a potent new weapon: a cell-wall-busting compound that leaves the microbe naked and vulnerable.

Dr. Mary Jackson and Dr. Mike McNeil, both professors in the Department of Microbiology, Immunology and Pathology at CSU, discovered a compound that halts the growth of M. tuberculosis cell walls by interfering with the transport of a key cell wall component: mycolic acids. The researchers reported their work in the March issue of Nature Chemical Biology. Other scientists have been trying to find mycolic acid transporters and ways to interfere with them for thirty years. A bacterium’s cell wall serves as a potent barrier to attack. Disabling the transporter mechanism “is like a factory making bricks and no way to get them to the construction site,” said McNeil. Jackson said, “We hope that our work also will pave the way to understanding what those transporters do in the cell and finding how to target them to kill the mycobacteria.”

Colorado State University has the largest TB research program in the nation. Approximately 150 people work on TB Vaccines, drugs, and tests. The National Institutes of Health’s National Institute of Allergy and Infectious Diseases funded the work. Drug companies find TB research unrewarding financially because the disease thrives in poor, third world countries, but resistant strains today travel easily in today’s global networks and often turn up next door. In March of this year 120 Longmont High School students and staff tested positive for the latent (dormant) form of TB.

“The next step,” said Jackson about her research, “is to optimize the chemistry of the compounds that we have found so that they eventually become one day novel antibiotics capable of treating TB in an infected patient. We need to move our discovery from the bench to the bedside.” Jackson also hopes to find other types of compounds so that they have more potential antibiotic bullets to hurl at this persistent microbe.

Developing new human treatments is a multi-step process that involves improving the chemistry of the compounds in the lab, making sure those compounds produce no side effects in humans, making sure they kill the TB microbe in an infected individual, and that they work as predicted in the final pharmacological formulation. “It’s a long route ahead,” said Jackson, “but this is what it takes to develop a new treatment.”

Jackson’s lab is also actively pursuing genetic work to unravel the mysteries of transporter action and how their compound blocks it. “This knowledge should considerably help us improve the compounds as we could focus on the aspects of their chemistry that makes them efficient instead of kind of ‘guessing.’”

Modern genetic work has also revealed interesting facts about the long and complicated history between humans, animals, and the enterprising TB microbe. German physician, Robert Koch (1843-1910), who discovered M. tuberculosis in 1882, also found a strain he named M. bovis that causes a similar disease in cows. While these two strains were considered species specific, genetic sequencing shows that the two species are 99.95% identical and that M. bovis evolved from M. tuberculosis and not the other way around. Early pastoralists may have infected cows 10-15,000 years ago.

Biologists, it seems, will never be out of work, as the subject of their labors morphs before their eyes. For now, we can celebrate the work of CSU’s microbiology department. They have breached the walls of the enemy, paving the way for a decisive assault that may end this long time scourge of mankind.

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