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Tim Born, biochemist and assistant professor in the Department of Chemistry,
studies enzymes to identify ones that could be new targets for antibacterial compounds
for new antibacterial drugs.
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Chemistry Department's Tim Born Battles Bacteria in the Lab
By Lynn Burke
When an adversary in battle is able to thwart an attack, a good strategist comes up with a new target to bring down that adversary's defenses. That's the line of reasoning behind some of the research of Tim Born, a biochemist and assistant professor in George Mason's Department of Chemistry. In Born's lab, the adversary is bacteria.
Born, who has been with George Mason since September 2000, says his major area of interest is the study of enzymes, proteins that catalyze nearly all chemical reactions within the human body. If the activity of key enzymes is inhibited, those reactions will not occur.
"Let's say you have a bacterial infection," Born explains. "You want to kill the bacteria so you need to stop something from happening within the bacteria that is crucial to their ability to survive. With antibacterial compounds, you can kill the bacteria or at least wound it enough so that your immune system can go ahead and clear things out." Many of these compounds target specific enzymes, inhibiting their activity.
"One of the major problems right now with antibacterial compounds is that there are a select number of targets, and we're using them on bacteria that have learned to deal with these attacks by modifying either their own enzymes or the drugs used to eliminate them," says Born. "Every time we design something new, resistance comes very quickly because it's already almost half in place." An example is penicillin. The bacteria that can't handle penicillin die, but the ones that can handle it live, resistant to the drug, as are all their progeny. "So the chemists tweak penicillin a bit, making it active again but probably not for long because the bacteria have already shown the ability to deal with this compound."
Born's strategy is to find something completely different to target that will catch bacteria by surprise. "One of the things that I'm starting to work on now is trying to identify enzymes that could be new targets for antibacterial compounds," says Born. "As it turns out, bacteria have some enzymes that we don't have, and we have a slightly different form of some of the enzymes that bacteria have." The objective, Born says, is to design specific inhibitors that would knock out the bacterial enzyme but not affect the human enzyme.
Born is looking at the pathways bacteria use to make methionine, an essential amino acid synthesized by bacteria. Methionine is required for bacterial growth, and its derivatives are used in other cellular reactions. "If you can knock out the ability of the bacteria to make methionine, you really limit it. Theoretically, the bacteria still are able to pick up the amino acid from the outside, but if they can't make it themselves, the bacteria can only grow at a very slow rate."
This particular pathway, the methionine biosynthetic pathway, does not have any current drugs designed against it, says Born, so the bacteria theoretically haven't seen anything that's going to inhibit this enzyme activity. "If we can design a compound that is brand new to them, it may take them a while to figure out how to get around it, which, with judicious use, could prevent resistance happening for a long time."
"I'm beginning to look at a couple of enzymes that are involved in the methionine biosynthetic pathway," he says. "We're really at step one right now. We've gotten purified enzyme and we're looking into its activity. We know what it does - that was the simple part. Now the hard part is, how does it do it? We know what it starts with and we know what it ends with. What happens in between?"
Answering that question could lead to the design of a molecule similar to that found in the intermediary step that could essentially mimic its activity. "The enzyme would bind to it, thinking that's what is supposed to happen, but when it gets there, it can't do anything more - it's stuck in that position and is shut down," says Born. That molecule could potentially be used as an antibacterial compound.
"I do want to stress that we're looking at very basic research right now," says Born. "We have a long way to go before actually having a new antibacterial drug." Even if such a molecule is designed, a number of questions would still need to be answered, not the least of which is, if it kills a bacterium, will it have a side effect on humans?
Even if what Born and his colleagues design doesn't work, he believes that just being able to validate the fact that the pathway can be inhibited would have a huge effect. "If our particular effort doesn't work, maybe someone else will look at it and say, in principle, stopping this pathway should work, so let's put some more effort in this and try to find something else." |
