Volume 4, Issue 33 November/December
Signaling an End to TB
Tom Alber, professor of molecular biology and biochemistry, is also a QB3 faculty affiliate. Photo by Melanie Brewer
HIV, SARS, and ebola may get the headlines, but among public health officials, tuberculosis is the pathogen to watch. Once routinely treated with cheap antibiotics, TB is poised to make a terrifying comeback.
More and more, doctors in developing nations are finding patients infected with strains of TB invulnerable to all but a handful of extremely expensive, exotic drugs. Worldwide, TB already infects one in every three people and sickens one in ten. Without new methods to stop the spread of drug-resistant strains, the cost of treating this ancient human pathogen could bankrupt even the most prosperous economies.
The environmental sensing enzymes in tuberculosis turn on when joined together. This mechanism activates the pathogen's defenses against the immune system. Image courtesy of Tom Alber
At Berkeley, Tom Alber is working to forestall this dire scenario. A professor of biochemistry and molecular biology, Alber is characterizing a class of enzymes TB uses to sense and adapt to its environment. Called protein phosphatases and protein kinases, they are essential components of the bacterium's invasion arsenal. By learning to subvert this system, Alber is developing a means to thwart even the most stubborn strains of TB.
So far, Alber has described the three-dimensional structure of more than a dozen of TB kinases and phosphatases. This has allowed him to piece together how these enzymes operate. He's found that their target molecules join two of the enzymes on the cell's exterior. Inside the cell, the lower halves of the enzymes lock together, too. "That's like shaking hands. All of a sudden they change shape, and that turns them on," Alber says.
The shape change triggers far-reaching shifts in the microbe's physiology. Activating one type of phosphate kinase, Alber has found, alters the expression of nearly 150 microbial genes.
The sensing enzymes in TB can trigger many changes in the bacterium's physiology. These include altering the expression of hundreds of genes as shown on this gene array chip. Image courtesty of Tom Alber
In addition to telling the bacterium whether it's in the water, languishing in soil, or inside a body, these enzymes also help TB to evade the immune system. In humans, the bacilli take up residence within the very cells out to kill them-the white blood cells, or macrophages, of the lungs. Normally, macrophages alert other cells to the presence of an invader. But TB, Alber discovered, pumps a phosphatase into the macrophage that seems to silence this alarm. For this reason, Alber says, "TB over decades can live in a macrophage and prevent it from ever knowing it's infected."
The same cloaking strategy could be at work in other pathogens. "Both TB and HIV live in immune system cells and may subvert the same molecules," says Alber, who has recently begun work on the virus that causes AIDS to see if there are commonalities between the two cloaking mechanisms.
More than 60 human pathogens, including deadly listeria and staphylococcus microbes, possess kinase and phosphatase enzymes, some of which are necessary for the microbes to cause disease. Alber's findings could lead to new classes of antibiotics for these pathogens as well.
After noticing commonalities in the defense mechanisms of HIV and TB, Alber expanded his research to include HIV. Photo courtesy of Tom Alber
Alber is now finding ways to inhibit these enzymes. Kinases and phosphatases are built along the same lines in both bacteria and humans. That means the vast libraries of molecules assembled to search for diabetes, pain, and cancer drugs could yield compounds that interfere with TB.
TB could, in theory, develop resistance to this new class of drugs, too. But Alber thinks he can skew the odds to favor humans. Identifying a drug capable of knocking out several TB enzymes at once could make it next to impossible for the bacterium to evolve resistance on multiple fronts.
Though TB is a daunting foe, Alber remains confident about the prospects of beating the disease. "As a bacterium, it should be easier to treat than HIV or malaria. Those kinds of diseases-caused by viruses and protozoans-we generally don't know how to cure," Alber says. "From a scientific perspective, TB is a simpler problem."