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Medicinal chemist Courtney Aldrich hopes to foil an old enemy with a novel class of antibiotics
By Mary Hoff
Dec. 5, 2006
It doesn't snarl, pounce or lurk in the shadows. It has no teeth or claws. Yet each day it claims more than 4,500 lives worldwide.
The deadly assailant is Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB). A century ago, TB--then commonly known as consumption--was often fatal. With the advent of streptomycin and other antibiotics in the 1940s and 1950s, humans began to gain the upper hand.
But any hint of victory was short-lived--today TB is the second leading cause of infectious disease mortality in the world. This is, in part, because of the lengthy and expensive regimen required to cure the disease (strict adherence to six to nine months of taking antibiotics), because of the rise in HIV/AIDS, which makes people more susceptible to the disease, and because of the emergence of multi-drug-resistant strains of TB.
"It's a huge global problem," says Courtney Aldrich, assistant director of the University's Center for Drug Design. Particularly challenging in his mind is the recent appearance of strains that have evolved to withstand two or more of the handful of antibiotics that are effective against the disease. "A relatively small percentage of all cases are multi-drug-resistant," he says, "but it's increasing, and it's increasing fairly rapidly."
Aldrich is out to do something about that. A chemist by training, he knows a lot about what M. tuberculosis needs to survive and thrive--and consequently, what just might do it in. With this knowledge he hopes to lead the way to developing a novel class of antibiotics that can step up to the plate when conventional approaches fail.
Aldrich has his eye on attacking M. tuberculosis at an entirely different Achilles' heel--its need for iron.Most antibiotics act by breaking down the bacterial cell wall or blocking the synthesis of DNA, RNA or proteins. Aldrich has his eye on attacking M. tuberculosis at an entirely different Achilles' heel--its need for iron. M. tuberculosis needs iron to carry out basic metabolic processes, and, like other bacteria, meets that need by grabbing iron from its host using claw-like molecules called siderophores. If he could find a compound that was harmless to humans but prevented siderophores from doing their job, Aldrich figures, M. tuberculosis would be in big trouble.
"Iron is essential. If you block anything involved in iron acquisition, I think it is a potential antibacterial," he says.
To that end, Aldrich has been studying the biochemical pathway M. tuberculosis uses to assemble the irongrabbing siderophores. He hopes to find a way to disrupt it using some simple and otherwise harmless chemical compound.
With U of M colleague Eric Bennett and Clifton Barry of the National Institutes of Health, he recently applied a "rational design" process to discover a promising target--an enzyme called MbtA that's not needed by mammals, but is indispensable to the siderophore production process--and to synthesize a compound that blocks MbtA's action. That work was so promising that he recently received an $897,000 NIH grant to search for and test the effectiveness of additional siderophore-synthesis inhibitors.
As his innovative approach progresses beyond the test-tube stage, Aldrich hopes in the next year or so that he and his team will zero in on a compound that is highly effective at blocking M. tuberculosis' access to iron--yet is safe for humans. At that point, he says, he would turn the project over to private-sector drug developers to move it through preclinical and clinical trials to eventual availability as a drug for the public.
"I think we have a good shot," he says.
From Pictures of Health, fall 2006, a publication for friends of the Academic Health Center.