Talk to Professor of Chemistry Rex Pratt about his research and you’ll get a crisp description of his field (biochemistry), his specialty (enzyme inhibitors), his research project (finding new molecular structures to make into antibiotics), and as much of the science behind it as you can understand. In Pratt’s office, a full-size Australian flag hanging in a back corner dominates the room. And as I interview him in the calm of his own office, noises spill in from his lab next door, where two students are at work; one student eventually pops her head in to see if he could answer a question.
Since Pratt came to Wesleyan 35 years ago, he has been studying beta-lactam antibiotics, a broad class of antibiotics including penicillins and cephalosporins. His research has been a continuous fight to stay a step ahead of rapidly evolving bacteria. Pratt and his team of eight post-docs, Ph.D. candidates, BA/MA students, and undergraduates are constantly finding and testing new molecular structures that have the same effect as other antibiotics but that the bacteria haven’t adapted to yet.
“[Bacteria] are all evolving and changing with time,” Pratt said. “We have a moving, fuzzy target.”
When Pratt’s lab synthesizes a new effective molecule, it’s up to the pharmaceutical companies to take it from there. They rarely do.
“Many are called, but few are chosen,” Pratt said.
However, while pharmaceutical companies may not always properly appreciate the importance of Pratt’s research, the National Institutes of Health has. He was just awarded a two-year grant worth $250,000 per year to continue his research.
In very general terms, Pratt’s research is based on the fact that a bacterium is surrounded by proteins with enzymes at its ends. These enzymes catalyze the reactions that build the cell wall, a structure that surrounds and protects the bacterium. Without their cell walls, bacteria are easily killed. Therefore, stopping these enzymes from working is the goal. Pratt’s lab works on inhibiting the enzymes that make the links that hold the cell wall together.
“The enzyme that we work on, this guy here that actually does the last step in the formation of these cross-bridges,” Pratt said, drawing a bacterium on a chalkboard in his office. “If you stop this enzyme then you stop all these cross-bridges, so the cell wall falls apart and eventually that bug falls apart, and it’s gone.”
Enzyme inhibitors work by clogging up the enzyme so that it can’t catalyze any more reactions. Pratt faces two particularly difficult problems in his task: not only are the bacteria constantly evolving to keep the antibiotics from clogging these enzymes, but they surround themselves with a cloud of decoy enzymes that are just like the enzymes making the cell wall. These beta-lactamases intercept the antibiotics, bind with them, and destroy them before they can clog up the cell wall-building enzymes. It’s not enough for Pratt’s new molecules to be able to clog up their intended enzymes, they have to be able to dodge these beta-lactamases as well. Finding out which molecules can do both is mostly trial and error.
“These things often occur through serendipity,” Pratt said.
Pratt fascination with chemistry is even older than his 35-year tenure at the University.
“I loved fooling around with chemicals from way back,” Pratt said. “It must be genetic. I fooled around with chemicals as a kid and made combustible rocket ship things with black powder and all sorts of things you’re not supposed to do nowadays… We did in high school have a chemistry club which met after school and did all sorts of horrible experiments that one would not be permitted to do nowadays.”
Even though the technology has only undergone a single significant change in Pratt’s 35 years at Wesleyan (he can now capture the enzymes he studies in crystalline form and see them directly), he is constantly keeping up with new developments, and his bookshelf is overflowing with books, new and old.
“You’re always looking for a new kind of molecule,” Pratt said. “So you’ve got to read widely, you’ve got to think broadly, you’ve got to look at the structures, you’ve got to look for analogies with other enzymes, you’ve got to follow organic chemistry, look for new chemical reactions, new elements, there’s a whole table of periodic elements that haven’t been exploited.”
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